Compounds and methods to treat cardiac failure and other disorders

ABSTRACT

Indoles, benzimidazoles and benztriazoles which are substituted at the 5 or 6 position with a substituent comprising an aromatic moiety linked through a piperazine ring to said indole, benzimidazole or benztriazole are useful in treating cardiac conditions associated with heart failure and in treating conditions characterized by proinflammation.

This application is a continuation in part of U.S. Ser. No. 09/275,176filed Mar. 24, 1999 now U.S. Pat. No. 6,340,685 which is acontinuation-in-part of U.S. Ser. No. 09/128,137 filed Aug. 3, 1998 nowU.S. Pat. No. 6,130,235 which application claims priority under 35U.S.C. 119(e) of provisional application No. 60/086,531 filed May 22,1998. The contents of these applications are incorporated herein byreference.

TECHNICAL FIELD

The invention is directed to compounds that are useful in treatinginflammation and that contain piperazine or piperidine moieties coupledto the 5- or 6-position of indole, benzimidazole or benzotriazole. Moreparticularly, the invention concerns novel ortho substituted indoles andN-substituted indoles as well as methods to treat heart and kidneyconditions using these compounds and derivatives thereof.

BACKGROUND ART

A large number of chronic and acute conditions have been recognized tobe associated with perturbation of the inflammatory response. A largenumber of cytokines participate in this response, including IL-1, IL-6,IL-8 and TNF. It appears that the activity of these cytokines in theregulation of inflammation rely at least in part on the activation of anenzyme on the cell signaling pathway, a member of the MAP kinase familygenerally known as p38 and alternatively known as CSBP and RK. Thiskinase is activated by dual phosphorylation after stimulation byphysiochemical stress, treatment with lipopolysaccharides or withproinflammatory cytokines such as IL-1 and TNF. Therefore, inhibitors ofthe kinase activity of p38 are useful antiinflammatory agents.

PCT applications WO98/28292, WO98/06715, WO98/07425, and WO96/40143, allof which are incorporated herein by reference, describe the relationshipof p38 kinase inhibitors with various disease states. As mentioned inthese applications, inhibitors of p38 kinase are useful in treating avariety of diseases associated with chronic inflammation. Theseapplications list rheumatoid arthritis, rheumatoid spondylitis,osteoarthritis, gouty arthritis and other arthritic conditions, sepsis,septic shock, endotoxic shock, Gram-negative sepsis, toxic shocksyndrome, asthma, adult respiratory distress syndrome, stroke,reperfusion injury, CNS injuries such as neural trauma and ischemia,psoriasis, restenosis, cerebral malaria, chronic pulmonary inflammatorydisease, silicosis, pulmonary sarcosis, bone resorption diseases such asosteoporosis, graft-versus-host reaction, Crohn's Disease, ulcerativecolitis including inflammatory bowel disease (IBD) and pyresis.

The above-referenced PCT applications disclose compounds which are p38kinase inhibitors said to be useful in treating these disease states.These compounds are either imidazoles or are indoles substituted at the3- or 4-position with a piperazine or piperidine ring linked through acarboxamide linkage. Additional compounds which are conjugates ofpiperazines with indoles are described as insecticides in WO97/26252,also incorporated herein by reference.

DISCLOSURE OF THE INVENTION

The invention is directed to compounds useful in treating inflammationgenerally, including specific conditions such as those described in theBackground section above. Certain novel compounds have been found toinhibit p38 kinase, in particular, p38 kinase α and are thus useful intreating diseases mediated by this enzyme. The compounds of theinvention are of the formula:

preferably those of the formulas:

and the pharmaceutically acceptable salts thereof,

wherein each Z¹ and Z² is independently CR⁴ or N;

where each R⁴ is independently H or is alkyl (1-6C) or aryl, each ofsaid alkyl or aryl optionally including one or more heteroatoms selectedfrom O, S and N and optionally substituted by one or more of halo, OR,SR, NR₂, RCO, COOR, CONR₂, OOCR, or NROCR where R is H or alkyl (1-6C),or by one or more CN or ═O, or by one or more aliphatic or aromatic 5-or 6-membered rings optionally containing 1-2 heteroatoms; or

two R⁴ taken together form a bridge optionally containing a heteroatom;

R¹ is

 wherein

X¹ is CO or an isostere thereof,

m is 0 or 1;

Y is optionally substituted alkyl, optionally substituted aryl, oroptionally substituted arylalkyl or two Y taken together may form analkylene (2-3C) bridge;

n is 0, 1 or 2;

Z³ is CH or N;

X² is CH, CH₂ or an isostere thereof; and

Ar consists of one or two phenyl moieties directly coupled to X²optionally substituted by halo, nitro, alkyl (1-6C), alkenyl (1-6C),alkynyl (1-6C), CN or CF₃, or by RCO, COOR, CONR₂, NR₂, OR, SR, OOCR orNROCR wherein R is H or alkyl (1-6C)

or by phenyl, itself optionally substituted by the foregoingsubstituents;

R² is H, or is alkyl (1-6C) or aryl each of said alkyl or aryloptionally including one or more heteroatoms which are O, S or N, andoptionally substituted by one or more of halo, OR, SR, NR₂, RCO, COOR,CONR₂, OOCR, or NROCR where R is H or alkyl (1-6C), or by one or more CNor ═O, or by one or more aliphatic or aromatic 5- or 6-membered ringsoptionally containing 1-2 heteroatoms;

R³ is H, halo, NO₂, alkyl (1-6C), alkenyl (1-6C), alkynyl (1-6C), CN,OR, SR, NR₂, RCO, COOR, CONR₂, OOCR, or NROCR where R is H or alkyl(1-6C).

Thus, in one aspect, the invention is directed to compounds of theformulas set forth above. In other aspects, the invention is directed tomethods to produce these compounds, to pharmaceutical compositionscontaining them, and to methods of treating inflammation using thesecompounds. The invention is also directed to treating conditionsassociated with cardiac failure using the invention compounds and othercompounds described herein.

Modes of Carrying Out the Invention

The compounds of formulas 1-4 are useful in a variety of physiologicalcontexts, as further described below. Preferred embodiments includethose wherein both Z¹ and Z² are CH or where Z¹ is CR⁴ and Z² is CH;thus, among the preferred compounds of the invention are derivatives ofindole. Especially preferred substituents at the 3-position are thosecoupled through carboxamide linkages. Thus, some preferred embodimentsof R⁴ are of the formula RNHCO— wherein R is alkyl or substituted alkyl.

In general, substituents on the nitrogen-containing portion of theindole, benzimidazole, or benztriazole nucleus are designed to enhancesolubility. Thus, typically, the substituents R² and R⁴ are polar orcontain polar groups.

In other preferred embodiments, the substituents shown for the compoundsof the invention are as set forth below.

In regard to R¹:

X¹ is CO or an isostere thereof. Thus, in addition to CO, X¹ may be CH₂,SO, SO₂, or CHOH. CO is preferred.

Z³ is CH or N; Z³=CH is preferred.

Typically m is 1; however, in some compounds of the invention, m can be0; thus, this substituent is a five-membered ring.

X² is CH₂ if Ar consists of a single phenyl moiety or CH if Ar consistsof two phenyl moieties or may be an isostere thereof. Thus, forappropriate embodiments of Ar, X² may be any of the alternatives setforth above for X¹.

The phenyl moieties represented by Ar may optionally be substituted bysubstituents including alkyl (1-6C), halo, RCO, COOR, CONR₂, OR, SR,NR₂, OOCR, NROCR, NO₂, CN, or CF₃, wherein R is H or alkyl (1-6C). Thephenyl moieties may also be substituted with an additional phenylresidue, preferably at the 4-position. The additional phenyl residue mayitself be substituted with the substituents set forth above. Theadditional phenyl may be substituted in all five positions, butpreferably less, preferably in 1-2 positions or not at all. Preferredsubstituents include alkyl (1-6C), OR, NR₂ and halo, especially halo andOCH₃. The substituents may occupy all five positions of the phenylsubstituent, preferably 1-2 positions or the phenyl may beunsubstituted.

n may be 0, 1 or 2, and is preferably 0. However, when n is 1, Y ispresent and may be alkyl, arylalkyl or aryl, all of which may optionallybe substituted by the substituents set forth above with regard to Ar.When n is 2, both Y groups together may constitute an alkylene bridge. Apreferred bridge is an ethylene bridge. Preferred embodiments of Y whenn is 1 include unsubstituted alkyl and unsubstituted arylalkyl.

With regard to R²:

R² is preferably H, but may also be a suitable substituent. Suchsubstituents are typically and preferably alkyl or substituted alkyl.The alkyl or substituted alkyl may optionally include one or moreheteroatoms which can be O, N or S, preferably N and O. Permittedsubstitutions on the alkyl group are set forth above; preferredsubstituents include OR, where R is H or alkyl (1-6C) and ═O. Alsoincluded among the preferred substituents on the alkyl group are cyclicmoieties, such as piperazine, pyridine, piperidine, phenyl, and thelike. Preferably, the alkyl embodiments of R² contain 0, 1 or 2substituents. Among preferred embodiments of R² are included those ofthe formula —(CO)O—Y′ wherein Y′ is, for example, —(CH₂)_(n)NR₂, where nis an integer of 0-6 and R is as defined above; or Y′ is, for example,an aliphatic or aromatic ring system, such as

Additional illustrative embodiments of R² include nicotinoyl and itsisomers, acryloyl, and substituents of the general formulaY′(CH₂)_(n)NH(CH₂)_(n)CHOH(CH₂)_(n)— wherein Y′ is a generic substituentsuch as optionally substituted alkyl, piperazinyl, piperidinyl,cyclohexyl, phenyl or methoxy, and the like and wherein each n isindependently an integer of 1-3. Y′ is quite variable and can generallyinclude any noninterfering moiety. Additional embodiments include thoseof the general formula Y′NH(CH₂)_(n)—CO, wherein Y′ and n are asdescribed above; also included are those of the general formulaY′(CH₂)_(n)NH(CH₂)_(n)CO where Y′ and n are as described above; andthose of the formula Y′(CH₂)_(n)CO and Y′(CH₂)_(n)NHCO, wherein Y′ and nare as defined above; and those of the formula R₂N(CH₂)_(n)— wherein Ris alkyl (1-6C) and n is an integer of 1-3.

With respect to R³:

Although R³ may be H, other embodiments are included and may bepreferred. These include halo, OR, NR₂, and alkyl (1-6C), asparticularly desirable.

In embodiments wherein Z¹ or Z², preferably Z¹, is CR⁴, where R⁴ isother than H, preferred embodiments of R⁴ include those of the formulaR₂N(CH₂)_(n)— wherein each R is independently alkyl (1-6C) or H and n isan integer of 1-6; or of the formula Y′(—CH₂)_(n)— wherein Y′ is asdefined above and n is an integer of 1-6; or those of the formulaY′NHCO; or those of the formula R₂NCO, wherein the R₂ substituents takentogether form a ring which may itself be substituted, preferably byalkyl arylalkyl, and the like. When R⁴ is Y′ (CH₂)_(n)—, for example, Y′may be

or R⁴ may be

Additional illustrative embodiments of R⁴ include 2-, 3- and 4-pyridyl,2-, 3- and 4-piperidyl.

The compounds of formulas (1)-(4) may be supplied in the form of theirpharmaceutically acceptable acid-addition salts including salts ofinorganic acids such as hydrochloric, sulfuric, hydrobromic, orphosphoric acid or salts of organic acids such as acetic, tartaric,succinic, benzoic, salicylic, and the like. If a carboxyl moiety ispresent, these compounds may also be supplied as a salt with apharmaceutically acceptable base, including inorganic bases such assodium hydroxide, potassium hydroxide, calcium hydroxide, ammoniumhydroxide and the like or a salt with a organic base such as caffeine.

Particularly preferred compounds of the invention are of formulas (5)and (6):

In these compounds, R¹ is of the formula shown, wherein each X³ isindependently halo, alkyl (1-6C), OR or NR₂, wherein R is H or alkyl(1-6C), and p is an integer of 0-3. R², R³ and R⁴ are as defined above.

Also preferred are similar compounds where the positions of R³ and theillustrated embodiment of R¹ are reversed; i.e., R³ is at position 5 andR¹ is in position 6.

Synthesis of the Invention Compounds

The compounds of the invention can be synthesized by a variety ofmethods most of them known in the art per se. The indole, benzimidazole,or benotriazole moiety may be supplied per se and the substituent R¹coupled thereto. R¹ may be supplied as such, or its synthesis may becompleted when the piperazyl or piperidyl residue is already coupled tothe indole, benzimidazole or benotriazole moiety. Alternatively,especially in embodiments wherein R³ represents a non-hydrogensubstituent, the appropriately substituted p-aminobenzoic acidderivative may be cyclized and then substituted with piperazine orpiperidine.

Thus, for example, as shown in Reaction Scheme 1, a piperazine protectedwith tert-butyloxycarbonyl (BOC) is coupled to 5-carboxybenzimidazole(or 5-carboxy-indole, or 5-carboxy-benzotrazole) in a reaction mixturecontaining a coupling agent such as EDAC in an inert, aprotic solvent toobtain the coupled carboxamide which is then deprotected and treatedwith substituted or unsubstituted benzyl halides or benzoyl halides.

R^(a)=for example, 2,6-difluorophenyl; 3,4-difluorophenyl;2,3-difluorophenyl; 3,5-difluorophenyl, 3-chlorophenyl; 4-chlorophenyl;4-carboxymethylphenyl; 4-methoxyphenyl; 4-trifluoromethyloxyphenyl;4-methylphenyl; 6-chloropiperonyl; t-butylcarboxyphenyl;3-trifluorophenyl; 2,4-dichlorophenyl; 3,4-dichlorophenyl; phenyl;methoxyphenyl; or p-toluyl.

Alternatively, as shown in Reaction Scheme 2, 5-carboxylatedbenzimidazole (or indole or benzotriazole) is reacted with a piperazineor piperidine moiety already substituted by X²—Ar. In this reaction, thepiperazyl or piperidyl derivative is directly reacted with thecarboxylated bicycloheteroatom-containing nucleus in the presence of acoupling agent such as EDAC in the presence of an inert solvent as setforth above.

In order to form the substituted piperazine required for Scheme 2,piperazine is first converted to the BOC derivative and then reactedwith ArCHO in the presence of a borohydride under acidic conditions togive the substituted piperazine as shown in Reaction Scheme 3.

An alternative for coupling derivatized piperazine or piperidine toindole, benzimidazole or benzotriazole is shown in Reaction Scheme 4. Inthis reaction, the piperazine or piperidine ring is derivatized to asuitable leaving group as shown and then treated with a base such as NaHin an inert solvent to obtain the desired conjugate.

Another alternative is shown in Reaction Scheme 5. In this approach, aprotected piperidone is reacted in the presence of base, such as NaH,with the appropriate phosphonate ester to obtain a protected benzylenepiperidine. The product is then deprotected and reacted with thecarboxylate of indole, benzimidazole or benzotriazole using anappropriate dehydrating agent. The product is then reduced to thedesired arylalkylated piperidine derivative.

Reaction Scheme 6 illustrates a method for preparing compounds of theinvention in which the indole is substituted in the 6-membered ringthereof. In Reaction Scheme 6, the appropriately substituted aniline isreacted with 1-methylmercaptyl-2,2-dialkoxyethane in the presence oftertiary butyryl chloride and base to provide the desired indole.Depending on the nature of the substitution of the aniline startingmaterial, more than one isomer may result as shown. The methylmercaptylgroup remaining on the 5-membered ring is reduced with Raney nickel anda mandatory methyl group included on the original aniline moiety ishydrolyzed to the corresponding carboxylic acid. The resulting acid isthen reacted with the desired piperidine or piperazine derivative in thepresence of a coupling agent such as EDC.

Alkylation of the nitrogens on the indole, benzimidazole orbenzotriazole nucleus in the compounds per se is carried out byconventional means by reacting the halide of the substituent to be addedin the presence of base and acetone, as shown in the illustrativealternative depictions of Scheme 7.

where X=H, OMe, Cl;

each R is H or alkyl;

n is an integer; or

 where X=H, OHC₃, Cl, CH₃, etc.;

each R is H, alkyl, aryl

or together both R form

Substituents at the 3-position of indole can be modified using thegeneral procedures shown in Scheme 8:

where X=OMe, Cl, CH₃;

each R is H, alkyl, aryl or together the R groups are piperazinyl,4-benzylpiperazinyl, etc.

Alternatively, Scheme 9 can be used:

For synthesis of compounds wherein n is I—i.e., wherein the piperidinering contains one additional substituent other than those mandated inthe compounds of the invention, the 4-substituted piperidine is firstprotected using BOC₂O in THF or other aprotic solvent and then reactedwith, for example, an alkyl iodide in the presence of S-butyllithium/TMEDA using, for example, ether as a solvent to produce thealkylated piperidine. The alkylated piperidine is then converted to theinvention compound by deprotection followed by formation of thecarboxamido linkage to the indoyl residue. This is exemplified below.

For compounds of the invention that are indoles substituted at the3-position, the Reaction Scheme shown at the beginning of Example 23 mayconveniently be used. Typically, the carboxamide starting material istreated with trifluoroacetic anhydride to obtain the trifluoroacetylintermediate, which is also a compound of the invention. Upon treatmentwith base, the 3-carboxylic acid is formed which can then be reactedwith a suitable amine to obtain additional compounds of the invention.

Administration and Use

The compounds of the invention are useful in treating conditionsassociated with inflammation. Thus, the compounds of formulas (1)-(4) ortheir pharmaceutically acceptable salts are used in the manufacture of amedicament for prophylactic or therapeutic treatment of mammals,including humans, in respect of conditions characterized by excessiveproduction of cytokines and/or inappropriate or unregulated cytokineactivity on such cells as cardiomyocytes, cardiofibroblasts andmacrophages.

The compounds of the invention inhibit the production of cytokines suchas TNF, IL-1, IL-6 and IL-8, cytokines that are importantproinflammatory constituents in many different disease states andsyndromes. Thus, inhibition of these cytokines has benefit incontrolling and mitigating many diseases. The compounds of the inventionare shown herein to inhibit a member of the MAP kinase family variouslycalled p38 MAPK (or p38), CSBP, or SAPK-2. The activation of thisprotein has been shown to regulate the production of prostanoids, suchas PGE2, and matrix metalloproteinases, such as collagenase-3, and toaccompany exacerbation of the diseases in response to stress caused, forexample, by treatment with lipopolysaccharides or cytokines such as TNFand IL-1. Inhibition of p38 activity, therefore, is predictive of theability of a medicament to provide a beneficial effect in treatingdiseases such as coronary artery disease, congestive heart failure,cardiomyopathy, myocarditis, vasculitis, restenosis, such as occursfollowing coronary angioplasty, atherosclerosis, rheumatoid arthritis,rheumatoid spondylitis, osteoarthritis, gouty arthritis and otherarthritic conditions, multiple sclerosis, acute respiratory distresssyndrome (ARDS), asthma, chronic obstructive pulmonary disease (COPD),silicosis, pulmonary sarcosis, sepsis, septic shock, endotoxic shock,toxic shock syndrome, heart and brain failure (stroke) that arecharacterized by ischemia and reperfusion injury, surgical procedures,such as transplantation procedures and graft rejections, cardiopulmonarybypass, coronary artery bypass graft, CNS injuries, including open andclosed head trauma, inflammatory eye conditions such as conjunctivitisand uveitis, acute renal failure, glomerulonephritis, inflammatory boweldiseases, such as Crohn's disease or ulcerative colitis, graft vs. hostdisease, bone resorption diseases like osteoporosis, type II diabetes,pyresis, psoriasis, cachexia, viral diseases such as those caused byHIV, CMV, and Herpes, and cerebral malaria, tumor metastases and acutepain, such as that accompanying dental surgery, dysmenorrhea andpost-orthopedic surgery.

Within the last several years, p38 has been shown to comprise a group ofMAP kinases designated p38α, p38β, p38γ and p38δ. Jiang, Y. et al. JBiol Chem (1996) 271:17920-17926 first reported characterization of p38βas a 372-amino acid protein closely related to p38α. Kumar, S. et al.Biochem Biophys Res Comm (1997) 235:533-538 and Stein, B. et al. J BiolChem (1997) 272:19509-19517 reported a second isoform of p38β, p38β2,containing 364 amino acids with 73% identity to p38α. All of thesereports show evidence that p38β is activated by proinflammatorycytokines and environmental stress, although the second reported p38βisoform, p38β2, appears to be preferentially expressed in the CNS, heartand skeletal muscle compared to the more ubiquitous, tissue expressionof p38α. Furthermore, activated transcription factor-2 (ATF-2) wasobserved to be a better substrate for p38β2 than for p38α, thussuggesting that separate mechanisms of action may be associated withthese forms. The physiological role of p38β1 has been called intoquestion by the latter two reports since it cannot be found in humantissue and does not exhibit appreciable kinase activity with thesubstrates of p38α.

The identification of p38γ was reported by Li, Z. et al. Biochem BiophysRes Comm (1996) 228:334-340 and of p38δ by Wang, X., et al., J Biol Chem(1997) 272:23668-23674 and by Kumar, S., et al., Biochem Biophys ResComm (1997) 235:533-538. The data suggest that these two p38 isoforms (γand δ) represent a unique subset of the MAPK family based on theirtissue expression patterns, substrate utilization, response to directand indirect stimuli, and susceptibility to kinase inhibitors.

Various results with regard to response to drugs targeting the p38family as between p38α and either the putative p38β1 or p38β2 or bothwere reported by Jiang, Kumar, and Stein cited above as well as byEyers, P. A. et al. Chem and Biol (1995) 5:321-328. An additional paperby Wang, Y. et al. J Biol Chem (1998) 273:2161-2168 suggests thesignificance of such differential effects. As pointed out by Wang, anumber of stimuli, such as myocardial infarction, hypertension, valvulardiseases, viral myocarditis, and dilated cardiomyopathy lead to anincrease in cardiac workload and elevated mechanical stress oncardiomyocytes. These are said to lead to an adaptive hypertrophicresponse which, if not controlled, has decidedly negative consequences.Wang cites previous studies which have shown that in ischemiareperfusion treated hearts, p38 MAPK activities are elevated inassociation with hypertrophy and programmed cell death. Wang shows inthe cited paper that activation of p38β activity results in hypertrophy,whereas activation of p38α activity leads to myocyte apoptosis. Thus,selective inhibition of p38α activity as compared to p38β activity willbe of benefit in treating conditions associated with cardiac failure.These conditions include congestive heart failure, cardiomyopathy,myocarditis, vasculitis, vascular restenosis, valvular disease,conditions associated with cardiopulmonary bypass, coronary arterybypass, grafts and vascular grafts. Further, to the extent that theα-isoform is toxic in other muscle cell types, α-selective inhibitorswould be useful for conditions associated with cachexia attributed toTNF or other conditions such as cancer, infection, or autoimmunedisease.

The compounds described herein which selectively inhibit the activity ofthe p38α isoform are useful for treating conditions associated withactivation of p38α, in particular those associated with cardiachypertrophy, ischemia or other environmental stress such as oxidationinjury, hyperosmolarity or other agents or factors that activate p38αkinase, or cardiac failure, for example, congestive heart failure,cardiomyopathy and myocarditis.

Compounds which exhibit this activity are of the formula

wherein R¹, R², R³, Z¹, and Z² are as defined in claim 1.

The manner of administration and formulation of the compounds describedherein will depend on the nature of the condition, the severity of thecondition, the particular subject to be treated, and the judgement ofthe practitioner; formulation will depend on mode of administration. Asthese compounds are small molecules, they are conveniently administeredby oral administration by compounding them with suitable pharmaceuticalexcipients so as to provide tablets, capsules, syrups, and the like.Suitable formulations for oral administration may also include minorcomponents such as buffers, flavoring agents and the like. Typically,the amount of active ingredient in the formulations will be in the rangeof 5%-95% of the total formulation, but wide variation is permitteddepending on the carrier. Suitable carriers include sucrose, pectin,magnesium stearate, lactose, peanut oil, olive oil, water, and the like.

The compounds useful in the invention may also be administered throughsuppositories or other transmucosal vehicles. Typically, suchformulations will include excipients that facilitate the passage of thecompound through the mucosa such as pharmaceutically acceptabledetergents.

The compounds may also be administered topically, for topical conditionssuch as psoriasis, or in formulation intended to penetrate the skin.These include lotions, creams, ointments and the like which can beformulated by known methods.

The compounds may also be administered by injection, includingintravenous, intramuscular, subcutaneous or intraperitoneal injection.Typical formulations for such use are liquid formulations in isotonicvehicles such as Hank's solution or Ringer's solution.

Alternative formulations include nasal sprays, liposomal formulations,slow-release formulations, and the like, as are known in the art.

Any suitable formulation may be used. A compendium of art-knownformulations is found in Remington's Pharmaceutical Sciences, latestedition, Mack Publishing Company, Easton, Pa. Reference to this manualis routine in the art.

The dosages of the compounds of the invention will depend on a number offactors which will vary from patient to patient. However, it is believedthat generally, the daily oral dosage will utilize 0.001-100 mg/kg totalbody weight, preferably from 0.01-25 50 mg/kg and more preferably about0.01 mg/kg-10 mg/kg. The dose regimen will vary, however, depending onthe conditions being treated and the judgment of the practitioner.

As implicated above, although the compounds of the invention may be usedin humans, they are also available for veterinary use in treating animalsubjects.

The following examples are intended to illustrate but not to limit theinvention.

Examples 1-3 illustrate Reaction Scheme 1:

EXAMPLE 1 Preparation of 4-BOC Piperazinyl-benzimidazole-5-carboxamide

Benzimidazole-5-carboxylic acid (3.25 g, 20 mMol) was reacted with 2.52g (20 mMol) diisopropylcarbodiimide in dry DMF at room temperature for15 minutes. To this reaction mixture was added 3.75 g (20 mMol)t-butyl-1-piperazine carboxylate, and the mixture was stirred for 18 h.The mixture was poured into water and extracted with methylene chloride(3×100 mL). The combined extracts were washed again with water, brineand dried over MgSO₄. After removal of the solvent in vacuo, the residuewas chromatographed on a column of silica gel eluting withCHCl₃-Methanol (gradient, methanol 0 to 5%) to yield 5.69 g (86%) of theproduct. ¹H-NMR (DMSO d₆): s 8.3 (1H); m 7.7-7.6 (2H), m 7.2-7.3 (1H), m3.6-3.3 (8H) s 1.4 (9H); MS (ESI) m/e 330 (m⁺).

EXAMPLE 2 Preparation of Piperazinyl-benzimidazole-5-carboxamide

The N-BOC piperazinyl-benzimidazole-5-carboxamide (5.6 g) was stirred in20 mL 4 Molar HCl-dioxane for 1 h. The dioxane was removed under reducedpressure to yield the hydrochloride salt in quantitative yield. This wasused for alkylations without any further purifications.

EXAMPLE 3 Preparation of4-(2,6-Difluorobenzyl)-piperazinyl-benzimidazole-5-carboxamide

A. Piperazinyl-benzimidazole-5-carboxamide (0.186 g, 0.5 mMol) was takenin 5 mL DMF and 0.101 g (1 mMol) triethylamine was added and stirred for15 minutes at room temperature. To this reaction mixture was added 0.104g 2,6-difluorobenzyl bromide and the mixture was stirred for 20 h. Thiswas poured into water and extracted with methylene chloride (3×50 mL).The combined extract was further washed with brine, water and dried overMgSO₄. The solvent was removed in vacuo and the residue chromatographedon silica gel eluting with chloroform-methanol (0 to 5% methanol,gradient). Evaporation of the desired fraction gave 48.9 mg of thedesired product; MS(ESI) m/e 356 (M⁺).

B. Using the procedure set forth in paragraph A, the following compoundswere prepared:

By substituting for 2,6-difluoro- Preparation of benzyl bromide:4-(2,3-difluorobenzyl)-piperazinyl-benzimidazole-5- 2,3-difluorobenzylcarboxamide MS (ESI) m/e 356 (M⁻) bromide4-(3,5-difluorobenzyl)-piperazinyl-benzimidazole-5- 3,5-difluorobenzyl-carboxamide MS (ESI) m/e 356 (M⁺) bromide4-(3-chlorobenzyl)-piperazinyl-benzimidazole-5- 3-chlorobenzylcarboxamide MS (ESI) m/e 354 (M⁺) bromide 4-(4-carboxymethylbenzyl)-piperazinyl-benzi- methyl-4-(bromo- midazole-5-carboxamide MS(ESI) m/e 378 (M⁺) methyl)-benzoate4-(4-methoxybenzyl)-piperazinyl-benzimidazole-5- 4-methoxybenzylcarboxamide MS (ESI) m/e 350 (M⁺) chloride4-(4-trifluoromethoxybenzyl)-piperazinyl-benzi- 4-(4-trifluoro-midazole-5-carboxamide MS (ESI) m/e 404 (M⁺) methoxy)-benzyl bromide4-(4-methylbenzyl)-piperazinyl-benzimidazole-5- 4-methylbenzylcarboxamide MS (ESI) m/e 334 (M⁺) bromide4-(2,4-dichlorobenzoyl)-piperazinyl-benzimidazole- 2,4-dichlorobenzoyl5-carboxamide MS (ESI) mle 403 (M⁺) chloride4-(3,4-dichlorobenzoyl)-piperazinyl-benzimidazole- 3,4-dichlorobenzoyl5-carboxamide MS (ESI) m/e 403 (M⁺) chloride4-[trans-3-(trifluoromethyl)-cinnamoyl]-piperazinyl- trans-3-(trifluoro-benzimidazole-5-carboxamide MS (ESI) m/e 428 methyl)-cinnamoyl (M⁺)chloride 4-(4-chlorobenzoyl)-piperazinyl-benzimidazole-5-4-chlorobenzoyl carboxamide MS (ESI) m/e 369 (M⁺) chloride4-benzoylpiperazine-benzimidazole-5-carboxamide benzoyl chloride MS(ESI) m/e 334 (M⁺) 4-(2-trifluoromethylbenzoyl)-piperazinyl-benzi-2-(trifluoro- midazole-5-carboxamide MS (ESI) m/e 402 methyl)-benzoyl(M⁻) chloride 4-(4-methxybenzoyl)-piperazinyl-benzimidazole-5-4-methoxybenzoyl carboxamide MS (ESI) m/e 364 (M⁺) chloride

Example 4 illustrates Reaction Scheme 2:

EXAMPLE 4 Preparation of4-(3,4-Dichlorophenyl)-piperazinyl-benzimidazole-5-carboxamide

A. Benzimidazole-5-carboxylic acid (1 mMol, 162 mg) was dissolved in 5mL dry DMF and reacted with1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride for 15minutes. 1-(3,4-dichlorophenyl)-piperazine, 1 mMol (231 mg) was addedfollowed by 10 mg DMAP. The mixture was stirred for 20 h at roomtemperature. The reaction mixture was poured into water and extractedwith methylene chloride (3×50 mL). The extracts were combined, washedwith brine, water and dried over MgSO₄. After evaporation of thesolvent, the residue was chromatographed on silica gel withchloroform-methanol (0-5% methanol, gradient). Evaporation of thedesired fractions gave 150 mg (40%) of the title compound; MS (ESI) m/e375 (M⁺).

Substituting for 1-(3,4-dichloro- Preparation of phenyl) piperazine,4-(4-chlorobenzhydryl)-piperazinyl-benzimidazole- 1-(4-chlorobenzhy-5-carboxamide MS (ESI) m/e 431 (M⁺) dryl)-piperazine 4-trans-1-cinnamylpiperazinyl-benzimidazole-5- trans-1-cinnamyl carboxamide MS (ESI) m/e346 (M⁺) piperazine 4-[bis(4-fluorophenyl)-methyl]-piperazinyl- 1-Bis(4-fluoro- benzimidazole-5-carboxamide MS (ESI) m/e 432 phenyl)-methyl(M⁺) piperazine 4-(4-chlorobenzyl)-piperazinyl-benzimidazole-5-1-(4-chlorobenzyl)- carboxamide MS (ESI) m/e 354 (M⁺) piperazine4-(2-chlorobenzyl)-piperazinyl-benzimidazole-5- 1-(2-chlorobenzyl)-carboxamide MS (ESI) m/e 354 (M⁺) piperazine4-benzylpiperazinyl-benzimidazole-5-carboxamide 1-benzyl piperazine MS(ESI) m/e 320 (M⁺)

Example 5 illustrates Reaction Scheme 3:

EXAMPLE 5 A. Preparation of4-(4-Methylthiobenzyl)-piperazinyl-benzimidazole-5-carboxamide

A mixture of 4-(methylthio)-benzaldehyde, 305 mg (2 mMol) and N-BOCpiperazine, 372 mg (2 mMol) was stirred in dry methanol for 30 minutes.To this mixture was added 1.6 g of polymer-supported borohydride (2.5mMol/g, on Amberlite, IRA-400, Aldrich) and the mixture was stirred for24 h. The polymer was removed by filtration and evaporation of thesolvent yielded the 4-BOC-1-(4-methylthio)-benzylpiperazine inquantitative yield. MS (ESI) m/e 322, (M⁺).

The 4-BOC-1-(4-methylthio)-benzylpiperazine was taken in 10 mL 1:1TFA/methylene chloride and stirred for 1 h at room temperature. Thesolvents were removed in vacuo and the residue was used withoutpurification for coupling with benzimidaiole-5-carboxylic acid.

Benzimidazole-5-carboxylic acid (2 mMol, 324 mg) was taken in 15 mL dryDMF and reacted with 2 mMol (382 mg) EDAC at room temperature for 15minutes. The above described 1-(4-methylthio)-benzylpiperazine was addedas a DMF solution followed by 505 mg (5 mMol) TEA. The mixture wasstirred for 20 h. The mixture was poured into water and extracted withmethylene chloride (3×50 mL). The combined extracts were washed withbrine, water and dried over MgSO₄. The solvent was removed in vacuo andthe residue was chromatographed. Evaporation of the desired fractionsgave the title compound; MS (ESI) m/e 366 (M⁺).

Substituting for 4-(methylthio)- Preparation of benzaldehyde4-(3,4,5-trimethoxybenzyl)-piperazynyl-benzimi- 3,4,5-methoxy-dazole-5-carboxamide MS (ESI) m/e 410 (M⁺) benzaldehyde4-(4-diethylaminobenzyl)-piperazinyl-benzimidazole- 4-diethylamino-5-carboxamide MS (ESI) m/e 391 (M⁺) benzaldehyde4-(biphenylmethyl)-piperazinyl-benzimidazole-5- 4-biphenylcarbox-carboxamide MS (ESI) m/e 396 (M⁺) aldehyde4-(4-Phenoxybenzyl)-piperazinyl-benzimidazole-5- 4-phenoxybenz-carboxamide MS (ESI) m/e 412 (M⁺) aldehyde

B. Preparation of 4-Benzyl-piperidinyl-benzimidazole-5-carboxamide

Benzimidazole-5-carboxylic acid (1.62 g, 10 mMol) was reacted with EDAC(1.92 g, 10 mMol) in 40 mL dry DMF at room temperature for 15 minutes.To the reaction mixture was added 4-benzylpiperidine (1.75 g, 10 mMol)and DMAP (˜20 mg, catalyst) and the mixture was stirred at roomtemperature for 20 h. It was poured into water and extracted withmethylene chloride (3-100 mL). The combined extract was washed withwater, brine and again with water. The extract was dried over MgSO₄ andevaporated. The residue was chromatographed on a column of silica gelwith chloroform-methanol (0 to 5% methanol). Evaporation of the desiredfractions gave 1.5 g (47%) of the product after recrystallization fromethyl acetate-hexane. ¹HNMR (CDCl₃): δ=7.8 (s, 1H); 7.1-7.3 (m, 8H);4.8-4.7 (broad m, 1H), 3.7-3.9 (broad m, 1H); 3.1-2.7 (broad m, 2H);2.55 (d, 2H); 2.0-1.1 (m, 5H). MS (ESI) m/e 319 (M⁺), 318 (M⁺−H).

EXAMPLE 6 Preparation of Additional Benzimidazole PiperidinylEmbodiments

The reaction scheme in this example is generally as follows:

2-Methoxy-3,4-dinitrobenzoic Acid:

4-Nitro-2-methoxybenzoic acid, 3.09 g, was added to 20 mL Nitricacid:Sulfuric acid 1:1, at 0° C. After addition was complete thereaction mixture was heated at 100 ° C. for 30 minutes. Cooled to roomtemperature and poured into 200 mL ice water. The aqueous layer wasextracted with ethyl acetate and washed with saturated sodium chloride,dried over anhydrous sodium sulfate and concentrated to give a yellowsolid. This material was purified by chromatography on silica usingethyl acetate/hexane/methanol/acetic acid 5/5/1/0.1. The yellow solidobtained was used for the next step. EIMS M⁺ 242 (Exp. 242). NMR, d₆DMSO: s (1H) 8.5, s (1H) 7.95, s (3H) 4.05.

2-Methoxy-3,4-diaminobenzoic Acid:

2-methoxy-3,4-dinitrobenzoic acid (1.0 g) was dissolved in methanol (50mL) and treated with 100 mg 10% palladium on carbon. The reactionmixture was purged with nitrogen and placed in an ice bath. Upontreatment with 5 mL formic acid, brisk effervescence was noticed whichsubsides upon further cooling. The reaction mixture was filtered throughcelite and concentrated to give a tan solid. (Decolorization occursrapidly upon keeping) EIMS M⁺ 182, Exp. 182.

6-Methoxy-5-benzimidazole Carboxylic Acid:

2-methoxy-3,4-diaminobenzoic acid, (0.5 g) was dissolved in 10 mL 90%aqueous formic acid. The mixture was brought to reflux and maintainedthere for 90 mins. Cooled to room temperature and the solvent removedunder pressure to give a dark solid. EIMS M⁺ 192, Exp. 192.

6-Methoxy-(4-benzylpiperidinyl)benzimidazole-5-carboxamide:

6-methoxy-5-benzimidazole carboxylic acid, (1 equivalent) was treatedwith 1.1 equivalent of EDAC.HCl and 1 equivalent of 4-benzylpiperidinein the presence of a catalytic amount of DMAP in DMF/DCM 1:1 for 3-6hrs. The reaction mixture was then concentrated and taken up in ethylacetate. After washing with 5% aq. Sodium carbonate and a solution ofsaturated sodium chloride, the organic layer was dried over anhydroussodium sulfate and concentrated to give crude material. This crudematerial was purified by chromatography on silica. M⁺ 349, Exp. 349.

6-Chloro-(4-benzylpiperidinyl)benzimidazole-5-carboxamide:

was prepared similarly. MH⁺ 353, Exp. 353.

EXAMPLE 7 N-Preparation of4-Benzyl-piperidinyl-benzimidazole-5-carboxamide

4-(4-Benzyl)-piperidinyl-benzimidazole-5-carboxamide (318 mg, 1 mMol)was taken in 20 mL acetone. KOH (solid, 280 mg, 5 mMol) was addedfollowed by 2-iodopropane (1 g˜6 mMol) and the mixture was refluxed for20 h. The acetone was removed in vacuo and the residue extracted fromwater with methylene chloride (3×50 mL). The extract was dried,evaporated and the residue chromatographed on silica gel withCHCL₃-Methanol (0 to 3% methanol). MS (ESI) m/e 360 (M⁺). HPLC: (VydacC18 column, 5 to 40% acetonitrile/water containing 0.1% TFA) two peaksshowing both isomers.

EXAMPLE 8 Preparation of 4-Benzylpiperidinyl-indole-5-carboxamide

Indole-5-carboxylic acid (1.61 g, 10 mMol) was reacted with EDAC (1.92g, 10 mMol) in 40 mL dry DMF for 15 minutes. 4-Benzylpiperidine (1.75 g,10 mMol) was added followed by DMAP (20 mg, catalyst) and the reactionmixture was stirred for 20 h. The mixture was poured into water andextracted with methylene chloride (3×100 mL). The combined extract waswashed with dilute hydrochloric acid, saturated sodium bicarbonate andwater and dried over MgSO₄. After evaporation of the solvent, theresidue was chromatographed with methylene chloride-methanol (0 to 2%methanol, gradient) to yield 1.60 g (50%) of the product afterrecrystallization from ether-Hexane.

MS (ESI) m/e 318 (M⁺), (317⁺−H). ¹HNMR (CDCl₃) δ=8.5 (s, 1H); 7.7 (s,1H); 7.4-7.15 (m, 8H); 6.8 (s, 1H); 4.8-4.6 (br, m, 1H); 4.1-3.9 9 br,m, 1H); 3.1-2.7 (br, m, 2H); 2.6 (d, 2H); 1.9-1.7 (br, m, 3H); 1.4-1,2(br, m, 2H).

EXAMPLE 9 Preparation of4-Benzylpiperidinyl-1-(2-propyl)-indole-5-carboxamide

A mixture of 4-benzylpiperidinyl-benzimidazole-5-carboxamide (318 mg, 1mMol), solid KOH (280 mg, 5 mMol) and 2-iodopropane (1 g, 6 mMol) wasrefluxed in 20 mL acetone for 20 h. After the removal of acetone invacuo, the residue was extracted from water with methylene chloride(3×50 mL). The combined extract was dried, evaporated andchromatographed to yield 180 mg (50%) of the desired product.

¹HNMR (CDCl₃): δ=7.7 (s, 1H); 7.4-7.1 (m, 7H); 4.8-4.6 (m, 1H); 3.0-2.7(br, m 2.6 (d, 2H); 1.8-1.45 (m, 3H); 1.5 (d, 6H); 1.3-1.1 (m, 2H). MS(ESI) m/e 360 (M).

EXAMPLE 10 Preparation of4-(4-Chlorobenzyl)-piperazinyl-1-(2-propyl)-indole-5-carboxamide

4-(4-Chlorobenzyl)piperazinyl-indole-5-carboxamide (420 mg, 1.32 mMol)was taken in acetone. Solid KOH (280 mg, 5 mMol) was added followed bythe addition of 2-iodopropane (1 g, 6 mMol) and the mixture was refluxedwith stirring for 20 h. Acetone was removed in vacuo and the residue wasextracted from water using methylene chloride. The extract was dried andevaporated and the residue was chromatographed on a column of silica gelusing ethylacetate-hexane (ethylacetate 0 to 25%, gradient) andrecrystallized from ether-hexane to yield 300 mg of the product. ¹HNMR(CDCl₃): δ=7.6 (s, 1H); 7.3-7.1 (m, 6H); 6.5 (s, 1H); 4.65-4.55 (m, 1H);3.8-3.5 (m, 4H); 3.4 (s, 2H); 2.4-2.5 (s, 4H); 1.5 (d, 6H). MS (ESI) m/e395 (M⁺).

EXAMPLE 11 Preparation of Additional Analogs

Using the procedure set forth in Example 8, but substituting forPreparation of indole-5-carboxylic acid4-benzylpiperidinyl-indole-6-carboxamide Indole-6-carboxylic acid MS(ESI) m/e 318 (M⁺), (317⁺-H) 4-benzylpiperidinyl-benzotriazole-5-carbox-Benzotriazole-5-carb- amide MS (ESI) m/e 320 (M⁺), (319⁺-H) oxylic acid

Using the procedure set forth in Example 11, but substitut- ing for4-chlorobenzyl piperi- Preparation of dinyl indole-5-carboxamide4-benzylpiperidinyl-1-(2-propyl)-indole-6- 4-benzylpiperidinyl-indole-6- carboxamide MS (ESI) m/e 360 (M⁺) carboxamide4-benzylpiperidinyl-1-(2-propyl)- 4-benzyl piperidinyl-benzotri-benzotriazole-5-carboxamide azole-5-carboxamide

EXAMPLE 12 Preparation of4-(3-Chlorobenzyl)-piperazinyl-N-benzyl-benzimidazole-5- and6-Carboxamides

A. This paragraph describes the procedure for formation of the N-benzylderivatives of the compounds of the invention; succeeding paragraphsdescribe alkylation with other moieties.

(4-(3-Chlorobenzyl)-piperazinyl-benzimidazole-5-carboxamide (0.12 g,0.33 mMol) and the benzyl bromide (0.058 g, 0.33 mMol) in 15 mL DMF werecombined with K₂CO₃ (0.09 g, 0.66 mMol). The mixture was stirred at RTovernight, then heated at 45° C. for 3 h. EtOAc was added and washedwith water. The organic layer was evaporated and the isomers wereseparated by silica gel column chromatography using 5% MeOH in EtOAc. ofisomer a (70 mg, 48%), MS (ESI) m/e 444 (M⁺) and of isomer b (40 mg,27%), MS (ESI) m/e 444 (M⁺) were obtained.

Similar treatment of the 6-carboxamide yields the corresponding compoundwhere R² is benzyl.

B. 4-(3-Chlorobenzyl)-piperazinyl-N-(2-propyl)-benzimidazole-5- and6-Carboxamides.

4-(3-Chlorobenzyl)-piperazinyl-benzimidazole-5-carboxamide was alkylatedsubstituting 2-iodopropane for benzyl bromide in paragraph A. Theisomers were separated using the same chromatographic conditions. Isomera, MS (ESI) m/e 396 (M⁺); isomer b, MS (ESI) m/e 396 (M⁺).

Similar treatment of the 6-carboxamide yields the corresponding compoundwhere R² is 2-propyl.

C. 4-(3-Chlorobenzyl)-piperazinyl-N-methyl-benzimidazole-5- andCarboxamide

4-(3-Chlorobenzyl)-piperazinyl)-benzimidazole-5-carboxamide wasalkylated substituting iodomethane for benzyl bromide in the procedureof paragraph A. The isomers were separated using silica gel columnchromatography using 50% acetone in acetonitrile as the eluting solvent.Isomer a, MS (ESI) m/e 368 (M⁺), isomer b, MS (ESI) m/e 368 (M⁺).

Similar treatment of the 6-carboxamide yields the corresponding compoundwhere R² is methyl.

Similarly, 4-benzylpiperidinyl-(1-methyl)-indole-5-carboxamide (MS (ESI)m/e 332 (M⁺)) was prepared from4-benzylpiperidinyl-indole-5-carboxamide.

Similar treatment of the 6-carboxamide yields the corresponding compoundwhere R² is methyl.

D. 4-(3-Chlorobenzyl)-piperazinyl-N-ethyl-benzimidazole-5- and6-Carboxamides

4-(3-Chlorobenzyl)-piperazinyl-benzimidazole-5-carboxamide was alkylatedsubstituting iodoethane for benzyl bromide in paragraph A. Isomer a, MS(ESI) m/e 382 (M⁺); isomer b, MS (ESI) m/e 382 (M⁺).

Similar treatment of the 6-carboxamide yields the corresponding compoundwhere R² is ethyl.

Similarly, 4-benzylpiperidinyl-(1-ethyl)-indole-5-carboxamide (MS (ESI)m/e 346 (M⁺)) was prepared from4-benzylpiperidinyl-indole-5-carboxamide.

Similar treatment of the 6-carboxamide yields the corresponding compoundwhere R² is ethyl.

EXAMPLE 13 Preparation of4-(4-Chlorobenzyl)-piperidinyl-indole-5-carboxamide

This example illustrates Reaction Scheme 5.

A. Preparation of N-BOC-4-(4-Chlorobenzylene)-piperidine

N-BOC-4-piperidone (2.0 g; 10 mmol) was taken withdiethyl-4-chlorobenzylphosphonate (2.6 g; 10 mmol) in dry THF. Sodiumhydride (400 mg, 60% dispersion in mineral oil; 10 mmol) was added andthe mixture was refluxed for three hr. The THF was removed in vacuo andthe residue extracted from water with methylene chloride. The extractwas dried over MgSO₄, evaporated and the residue was chromatographed onsilica gel to yield 0.615 g of the desired product. ¹HNMR (CDCl₃): δ=7.3(d, 2H); 7.1 (d, 2H); 6.3 (s, 1H); 3.55-3.50 (m, 2H); 3.45-3.35 (m, 2H);2.45-2.35 (m, 2H); 2.30-2.25 (m, 2H); 1.25 (s, 9H). EIMS: 307 (M⁺), 251(M⁺−C3H8).

B. Coupling of 4-Chlorobenzylene Piperidine With Indole-5-carboxylicAcid

The N-BOC-4-(4-chlorobenzylene-piperidine, described above, wasdeprotected by stirring in 20 mL 1:1 dichloromethane-trifluoroaceticacid for 1 h. It was evaporated and dried in vacuo for 1 h to remove alltraces of trifluoroacetic acid. It was redissolved in 15 mLdichloromethane and the TFA salt was neutralized by the addition of aslight excess of triethylamine. Solution A.

Indole-5-carboxylic acid 0.32 g (2 mmol) was reacted with 0.383 g EDACin 30 mL dry dichloromethane for 15 minutes. To this solution was addedthe methylene chloride solution of 4-chlorobenzylene-piperidine(solution A) followed by the addition of 10 mg of DMAP. The mixture wasstirred for 20 h. The mixture was washed with water, 2N HCl, 5% sodiumcarbonate and then water. The organic solution was dried, evaporated andthe residue was chromatographed on silica gel eluting withethylacetate-hexane (1:4). Yield: 260 mg (37%). EIMS: 350 (M⁺), 315(M⁺−Cl) ¹HNMR (CDCl₃): δ=8.4 (s, 1H); 7.7 (s, 1H); 7.3-7.0 (m, 7H); 6.5(s, 1H); 6.25 (s, 1H); 3.8-3.0 (m, br, 4H); 2.6-2.20 (m, br, 4H).

C. Hydrogenation of4-(4-Chlorobenzylene)-piperidine-indole-5-carboxamide

4-(4-Chlorobenzylene)-piperidine-indole-5-carboxamide (240 mg, 0.68mmol) was dissolved in 40 mL THF. Pd/C (25 mg) was added and the mixturewas hydrogenated (1 atm) for 20 h with rapid stirring. The catalyst wasremoved by filtration through celite and the organic solution wasevaporated and the residue was recrystallized from methylenechloride/hexane. Quantitative yield. EIMS: 352 (M⁺), 351 (M⁺−H).

EXAMPLE 14

Substituting for 4-chlorobenzyl Preparation of piperidine4-(3-chlorobenzyl)-piperidinyl-indole-5-carboxamide 3-chlorobenzyl MS(ESI) m/e 353 (M⁺) piperidine4-(2-chlorobenzyl)-piperidinyl-indole-5-carboxamide 2-chlorobenzyl MS(ESI) m/e 353 (M⁺) piperidine

EXAMPLE 15 Synthesis ofcis-2-Methyl-4-benzylpiperidin-1-yl-indole-5-carboxamide

A. A mixture of 4-benzylpiperidine (3.52 mL, 20.0 mMol) anddi-tert-butyl-dicarbonate (5.45 g, 25.0 mMol) in 100 mL of THF wasrefluxed for 20 h. After cooling to rt the reaction mixture was pouredinto water and extracted with ethyl acetate (2×100 mL), the combinedorganic extract was washed with water and brine. The extract was driedover Na₂SO₄ and evaporated. The residue was chromatographed on a columnof silica gel with 10% ethyl acetate-hexane. Evaporation of the desiredfractions gave 5.02 g (91%) of the product as an oil. MS (ESI) m/e 275(M⁺).

B. A mixture of 1-BOC-4-benzylpiperidine (0.825 g, 3.0 mMol) andN,N,N′,N′,-tetramethylethylenediamine (TMEDA) (0.59 mL, 3.9 mMol) in 6mL of Et₂O was cooled to −78° C. under argon. A 1.3M solution of s-BuLiin cyclohexane (3.0 mL, 3.9 mMol), was added dropwise. After theaddition was complete, the reaction mixture was stirred at −20° C. for30 min and cooled back to −78° C. Methyl iodide (0.28 mL, 4.5 mMol) wasadded and the reaction mixture was stirred at −78° C. for 5 min, thecooling bath removed and stirring was continued an additional 3 min. Thereaction mixture was poured into water and extracted with ethyl acetate(2×25 mL). The combined organic extract was washed with water and brine.The extract was dried over Na₂SO₄ and evaporated to give 0.58 g (67%) ofan oil that was one spot by TLC (silica gel, 10% ethyl acetate-hexane).This material was used directly in the next step. MS (ESI) m/e 289 (M⁺).

C. To a solution of 1-BOC-2-methyl-4-benzylpiperidine (0.29 g, 1.0 mMol)in 5 mL of dichloromethane was added trifluoroacetic acid (TFA) (0.5mL). After stirring at rt for 10 h the reaction mixture was evaporatedin vacuo and azeotroped twice with dichloromethane and twice withhexane. The residue was dissolved in 5 mL of dichloromethane anddiisopropylethylamine (1.6 mL, 10 mMol) was added. In a separate flask amixture of 5-indolecarboxylic acid (0.19 g, 1.2 mMol) and EDAC (0.23 g,1.2 mMol) was dissolved in 15 mL of dichloromethane and stirred at rtfor 5 min. To this reaction mixture was added the first solution, andthe resulting mixture stirred at rt for 20 h. The reaction mixture waspoured into water and extracted with ethyl acetate (2×50 mL). Thecombined organic extract was washed with water and brine. The extractwas dried over Na₂SO₄ and evaporated. The residue was chromatographed ona column of silica gel with 1% MeOH-dichloromethane. Evaporation of thedesired fractions gave 0.18 g (54%) of the product as an oil.

When tested as described below, the title compound has an IC₅₀=280 nM.

EXAMPLE 16 Preparation of4-Chloro-(4-benzylpiperidinyl)indole-5-carboxamide and6-Chloro-(4-benzylpiperidinyl)indole-5-carboxamide

A. The indole synthesis was accomplished by the method of Gassman, P. G.J Am Chem Soc (1974) 96: 5495-5507. To a solution of 2.0 g (10.8 mmol)of 4-amino-2-chloro methylbenzoate in 30 mL CH₂Cl₂ at −60° C. was added1.2 g (10.8 mmol) of t-butyl hypochlorite in 20 mL of CH₂Cl₂. After 10min. 10.8 mmol of methylthioacetaldehyde dimethyl acetal in 10 ml ofCH₂Cl₂ was added, stirring at −60° C. continued for 1 h.

Subsequently, 10.8 mmol of Et₃N in 10 ml CH₂Cl₂ was added and thesolution was allowed to warm to room temperature. The solvent wasevaporated and the residue was dissolved in 30 mL CCl₄, 5 mL of Et₃N wasadded and the mixture was refluxed for 4 h. The solvent was removed andthe residue was dissolved in 50 mL of ether. Cyclization of the acetalto indole was effected by stirring this solution for 3 h with 20 mL of 2N HCl. The ethereal layer was washed with saturated NaHCO₃, dried,filtered and evaporated. The isomeric indoles were separated by columnchromatography on silica gel. The structure of the isomers wasidentified by NMR spectroscopy. Isomer a:5-carboxymethyl-4-chloro-3-thiomethylindole, ¹H NMR (CDCl₃). 6 2.35 (s,3H), 3.95 (s, 3H), 7.32 (s, 1H), 7.42 (s, 1H), 8.33 (s, 1H), 8.61 (s,1H). Isomer b: 5-carboxymethyl-6-chloro-3-thiomethylindole, ¹H NMR(CDCl₃) δ 2.42 (s, 3H), 3.97 (s, 3H), 7.20 (s, 1H), 7.25 (d, 1H), 7.71(d, 1H), 8.58 (s, 1H).

A solution of 100 mg of 5-carboxymethyl-4-chloro-3-thiomethylindole(isomer a) in 10 mL of ethanol was treated with W-2 Raney nickel untildethiomethylation was completed. The indole ester isolated was treatedwith NaOH in methanol:water (1:1) and thereby 60 mg of4-chloroindole-5-carboxylic acid was isolated as a white solid, ¹H NMR(DMSO-d₆) δ d 6.61 (s, 1H), 7.41 (d, 1H), 7.52 (s, 1H), 7.62 (d, 1H),11.62 (s, 1H).

To a solution of 50 mg (0.25 mmol) of above indole acid in 10 mL of DMFwas added 50 mg (0.28 mmol) of 4-benzylpiperidine and 60 mg (0.28 mmol)of EDAC. The reaction mixture was stirred overnight, diluted with ethylacetate and washed with water. the organic layer was dried, filtered andevaporated to get a white solid. This was purified by silica gelchromatography followed by crystallization to obtain 50 mg of4-chloro-5-(4-benzylpiperidinyl)-indole carboxamide as a white solid, MS(M⁺ 352).

Isomer b was converted to 6-chloroindole-5-carboxylic acid using thesame reaction sequence as described above and was coupled to4-benzylpiperidine to obtain 6-chloro-5-(4-benzylpiperidinyl)-indolecarboxamide as a white solid, MS (M⁺ 352).

B. Using the method of paragraph A,4-Chloro-(4-(4-fluorobenzyl)piperidinyl)indole-5-carboxamide and6-Chloro-(4-(4-fluorobenzyl)piperidinyl)indole-5-carboxamide wereprepared.

EXAMPLE 17 The Corresponding 6-Piperidinyl Indole Derivatives

Compounds similar to those in paragraphs A and B of Example 16, butwherein the piperidinyl substituent is at the 6-position are synthesizedas follows:

a) Methanol, thionyl chloride, reflux

b)

i) N-chlorosuccinimide, DCM, methylthioacetaldehyde dimethylacetal,triethylamine, reflux

ii) CHCl₃, reflux

iii) HCl

c) Raney Ni, EtOH

d) Methanol, sodium hydroxide, reflux

e) Benzylpiperidine, EDA.CHCl, DMAP, DMF/DCM.

f) Acetone, potassium hydroxide, nicotinoyl chloride.

Specifically, the following compounds were prepared according to thismethod:

4-Benzylpiperidinyl-5-chloroindole-6carboxamide:

MH⁺ 351, exp 352;

4-Benzylpiperidinyl-7-chloroindole-6-carboxamide:

MH⁺ 351, exp 352;

1-nicotinoyl-4-benzylpiperidinyl-7-chloroindole-6-carboxamide:

M⁻ 457, exp 457;

1-Nicotinoyl-3-(2-dimethylamino)ethyl AminoCarbonyl-4-benzylpiperidinyl-7-chloroindole-6-carboxamide:

MH⁺ 571, exp 571. (See Examples 19-21 for addition of substituents atpositions 1 and 3.)

EXAMPLE 18 Preparation of4-Methoxy-(4-benzylpiperidinyl)indole-5-carboxamide and6-Methoxy-(4-benzylpiperidinyl)indole-5-carboxamide

A. Preparation of 4-Methoxyindole and 6-methoxyindole-5-carboxylicAcids.

The corresponding methyl esters of these indole acids were prepared by amodified method of Scheme 6 according to Inoue, S. Heterocycles, (1992)34: 1017-1029, wherein the two isomeric indole acids were obtained in a3:2 ratio. 5-carboxymethyl-4-methoxyindole. ¹H NMR (CDCl₃) δ 2.42 (s,3H), 3.92 (s, 3H), 4.13 (s, 3H), 7.14 (d, 1H), 7.18 (d, 1H), 7.55 (d,1H), 9.41 (s, 1H). 5-Carboxymethyl 6-methoxyindole. ¹H NMR (CDCl₃) δ2.38 (s, 3H), 3.81 (s, 3H), 3.95 (s, 3H), 6.83 (s, 1H), 7.21 (s, 1H),8.22 (s, 1H), 8.50 (s, 1H).

B. Conversion to Title Compound

4-Methoxy or 6-methoxy-indole-5-carboxylic acid was coupled with4-benzylpiperidine to obtain the title compounds, MS (M⁺ 349).

In addition, 4-methoxy-indole-5-carboxylic acid was coupled with4-(4-fluorobenzyl)piperidine to obtain4-methoxy-(4-(4-fluorobenzyl)piperidinyl)indole-5-carboxamide, MS (M+367) and 6-methoxy-indole-5-carboxylic acid was coupled with4-(4-fluorobenzyl)piperidine to obtain6-methoxy-(4-(4fluorobenzyl)piperidinyl)indole-5-carboxamide. MS (M+367).

EXAMPLE 19 Preparation ofN-(3-Cyclohexylmethylamino-2-hydroxypropyl)-4-benzylpiperidinyl-indole-5-carboxamide

A. The title compound was prepared according to scheme 7. To an ice-coldsolution of 1.0 g (3.0 mmol) of 4-benzylpiperidinyl indole-5-carboxamidein acetone was added 15 mmol of powdered KOH followed by 3.0 mmol ofepibromohydrin and the mixture was stirred for 30 min. The mixture wasfiltered and the solution was evaporated. The residue was dissolved inethyl acetate, washed with water, dried and evaporated. Afterpurification by silica gel column chromatography 435 mg of epoxide wasobtained. MS (M⁺ 373).

To a solution of 200 mg (0.54 mmol) of the above indole epoxide in 5 mLof MeOH was added 121 mg (1.1 mmol) of cyclohexylmethylamine and themixture was refluxed for 1 hr. The crude product was purified on silicagel column. The amino compound was then converted into its HCl salt bytreating with ethanolic HCl. MS (M⁺ 487).

B. Following the procedure of paragraph A, but substituting piperazinefor cyclohexylmethylamine,N-(3-N-methylpiperazinyl-2-hydroxypropyl)-4-benzylpiperidinylindole-5-carboxamide:

was prepared. MS (M⁺ 473);

substituting benzylamine for cyclohexylmethylamineN-(3-benzylamino-2-hydroxypropyl)-4-benzylpiperidinylindole-5-carboxamide:

MS (M⁺ 481) was prepared;

substituting p-methoxybenzylamine for cyclohexylmethylamine,N-[3-{(4-methoxybenzyl)-amino}-2-hydroxypropyl-]5-(4-benzylpiperidinylindole-5-carboxamide:

MS (M+ 511) was prepared; and

substituting propylamine for cyclohexylmethylamine,N-{3-n-propylamino-2-hydroxypropyl}-4-benzylpiperidinylindole-5-carboxamide:

MS (M⁺) 433 was prepared.

EXAMPLE 20 Preparation of Additional 1-Substituted Derivatives

A. Preparation of N-(4-Pyridoyl)-4-benzylpiperidinylIndole-5-carboxamide

0.318 mg (1 mmol) of 4-benzylpiperidinyl indole-5-carboxamide wasdissolved in 15 mL dry DMF. 80 mg (60% suspension in oil) of sodiumhydride was added and the mixture was stirred for 30 minutes undernitrogen. The mixture was cooled to 0° C. and 200 mg (1.1 mmol)isonicotinyl chloride hydrochloride was added and the mixture wasstirred for 20 hr at room temperature. The reaction was quenched by theaddition of sat. ammonium chloride solution, diluted with water and theproduct was extracted with dichloromethane. The extract was dried,evaporated and the residue was chromatographed on silica gel (ethylacetate-hexane, gradient, 50-75% ethyl acetate) to yield 150 mg of thepure product. ESI MS (M⁺ 423, M⁺−H, 422).

Using the procedure of the previous paragraph, but substituting4-picolyl chloride hydrochloride for isonicotinyl chloridehydrochloride, N-(4-pyridylmethyl)-4-benzylpiperidinylindole-5-carboxamide:

MS (M+ 409) was prepared.

B. Preparation of1-Nicotinoyl-(4-benzylpiperidinyl)-indole-6-carboxamide:

This compound was prepared similarly. M⁺ 423.

C. Preparation of1-Nicotinoyl-6-methoxy-(4-benzylpiperidinyl)-indole-5-carboxamide:

This compound was prepared similarly. M⁺ 490.

D. Preparation of N-methylacetyl-4-Benzylpiperidinylindole-5-carboxamide and its free acid:

1.95 g (6.13 mmol) of 4-benzylpiperidinyl indole-5-carboxamide wasdissolved in 30 mL dry DMF and was treated with 320 mg (8 mmol, 60%suspension in oil) sodium hydride for 30 minutes. The reaction mixturewas cooled to 0° C. and 1.225 g (8 mmol) bromomethylacetate was addedand stirring continued for 1 h at 0° C. The ice-bath was removed andstirring continued for another 6 h at room temperature. The reaction wasquenched by the addition of sat. ammonium chloride solution, dilutedwith water and extracted with dichloromethane. The extract was dried,evaporated and the residue purified by column chromatography on silicagel eluting with ethylacetate-hexane (25-35% ethylacetate) to yield 2.2g (92%) of the desired product. MS: M⁺, 390; M⁺−1, 389.

¹HNMR (CDCl₃): □ 7.7 (s, 1H); 7.35-7.1 (m, 8H); 6.6 (s, 1H); 5.1 (s,2H); 3.75 (s, 3H); 3.0-2.7 (br, m, 4H); 2.6 (d, 2H); 1.9-1.2 9 m, 5H).

2.15 g, (5.5 mmol) of 4-Benzylpiperidinylindole-5-carboxamide-1-methylacetate from the previous paragraph wastaken in 20 mL ethanol . A solution of 2.0 g K₂CO₃ in 20 mL water wasadded and the mixture was refluxed for 2 h. The ethanol was removedunder reduced pressure, the remaining solution diluted with water andacidified with conc. HCl. The precipitated product was collected byfiltration, washed with water and dried to yield 1.9 g of the product.MS: M⁺, 376; M⁺−H, 375.

E. Preparation of 1-Acryloyl-(4-benzylpiperidinyl)-indole-5-carboxamide:

0.318 g (1 mmol) of (4-benzylpiperidinyl)-indole-5-carboxamide was takenin 15 mL dry acetone and was reacted with 0.2 g (5 mmol) of powdered KOHfor 15 Min. The mixture was cooled in ice and 0.225 mg (2.5 mmol) ofacryloyl chloride was added in one lot. Stirring continued at 0° C. for20 Min., after which the reaction was further stirred at room temp. for1 h. the solvent was removed in vacuo and the residue was extracted withethyl acetate from water. The extract was dried and evaporated. TLC(ethyl acetate-hexane) and mass spectrum (M⁺ at 372) confirmed thedesired product. This product was used without further purification forthe next step.

F. 1-[3-(2-Propylamino)-propionyl]-(4-benzylpiperidinyl)-5-indoleCarboxamide:

The above obtained product was dissolved in 20 mL dichloromethane andreacted with 0.1 mL, isopropylamine at room temperature for 18 h. Thesolvent was removed and the product was purified by columnchromatography on silica gel eluting with chloroform-methanol (95:5).Yield: 180 mg, M⁺, 431.

G. 1-Piperazinylpropionyl)-(4-benzyl)-piperidinyl-indole-5-carboxamide:

The 1-acryloyl-(4-benzyl)-piperidinyl-indole-5-carboxamide above wasreacted with tert-butyl-1-piperazine carboxylate as described before.The product was deprotected using methanolic HCl. M⁺ 458.

H. 1-(3-Benzylaminopropionyl)-(4benzylpiperidinyl)-indole-5-carboxamide:

was prepared by reacting1-acryloyl-(4-benzylpiperidinyl)-indole-5-carboxamide with benzylamine.M⁺ 479.

I.1-(3-Morpholinylpropionyl)-4-(4-benzylpiperidinyl)-indole-5-carboxamide

was prepared by reacting1-acryloyl-(4-benzylpiperidinyl)-indole-5-carboxamide with morpholine,M⁺ 459.

J. Preparation of 4-Benzylpiperidinyl Indole-5-carboxamide-1-aceticAcid-n-propylamide:

4-Benzylpiperidinyl-indole-5-carboxamide-1-acetic acid (200 mg, 0.53mmol) from Example 21 was reacted with 120 mg (0.61 mmol) EDC in 10 mLdry dichloromethane for 30 minutes. n-propylamine (100 μL, excess) wasadded and the mixture stirred for 20 h. The solution was diluted withdichloromethane, washed with water and 5% sodium carbonate solution. Theorganic solution was dried and evaporated and the residue purified bysilica gel chromatography with ethyl acetate-hexane (3:2) to yield 100mg of the product. MS (M⁺ 417).

K. Preparation of 4-Benzylpiperidinyl-indole-5-carboxamide-1-aceticAcid, (4-Methoxybenzyl)amide:

Following the procedure in the previous paragraph but substitutingp-methoxybenzylamine for n-propylamine,4-benzylpiperidinyl-indole-5-carboxamide-1-acetic acid,(4-methoxybenzyl) amide was prepared. MS, ESI: M+H, 496.

L. Preparation of1-(Diethylaminoethyl)-6-methoxy-(4-benzylpiperidinyl)-indole-5-carboxamide:

0.3 g (0.862 mmol) of6-methoxy-(4-benzylpiperidinyl)-indole-5-carboxamide was dissolved in 20mL dry DMF. It was cooled in an ice-bath and reacted with 0.12 g NaH (3mmol, 60% suspension). 0.172 mg (1 mmol ) of2-(diethylamino)-ethylchloride hydrochloride was added and the mixturewas stirred for 18 h. The reaction mixture was poured in to water andextracted with dichloromethane (3×75 mL). The combined extract waswashed again with water, dried over anhydrous MgSO₄, evaporated andpurified by silica gel chromatography on a chromatotron usingCH₂Cl₂-Methanol (95:5) to yield 0.22 g of the desired product. It wasconverted to the HCl salt and lyophilized, M⁺ 448.

M. Following the Procedure of the Previous Paragraph, but Substituting1-(Diethylamino)-n-propylchloride Hydrochloride for1-(Diethylamino)-ethylchloride Hydrochloride,1-(Diethylamino)n-propyl-(4-benzylpiperidinyl)-indole-5-carboxamide

was prepared. M⁺ 468.

Similarly,1-(Diethylamino)-ethyl-(4-benzylpiperidinyl)-indole-5-carboxamide,

was prepared, M+ 454.

Similarly,1-(Diethylamino)-n-propyl-6-chloro-(4-benzylpiperidinyl)-indole-5-carboxamide,

was prepared, M⁺ 502.

Similarly,1-(Diethylamino)-ethyl-(4′-fluoro-4-benzylpiperidinyl)-indole-5-carboxamide,

was prepared, M⁺, 472;

Also1-(Diethylamino)-n-propyl-6-methoxy-(4-benzylpiperidinyl)-indole-5-carboxamide,

was prepared, M⁺, 498.

EXAMPLE 21 Preparation of 3-Substituted Indoles

The general procedure for synthesis of the 3-substituted indoles isoutlined as follows:

A. 3-trifluoroacetyl-4-benzylpiperidinyl-indole-5-carboxamide: 4-benzylpiperidinyl-indole-5-carboxamide (1 eq.) was dissolved in anhydrous THF.The reaction vessel was purged with nitrogen and placed in an ice bath.Trifluoroacetic anhydride (1.2-1.3 eq. ) was added via syringe. Thereaction was allowed to continue at 0° C., until no more startingmaterial was discovered by thin layer chromatography. In some cases theaddition of additional trifluoroacetic anhydride was required tofacilitate the completion of the reaction. After completion of thereaction, the reaction mixture was concentrated and redissolved in theminimal amount of ethyl acetate for chromatography using silica. Thecrude material was chromatographed using ethyl acetate and hexanes(1:1). The identity of the product 3-trifluoroacetyl-4-benzylpiperidinyl indole-5-carboxamide was determined by electron impact massspectroscopy. (MH⁺ 413 (exp. 414, base peak 240.)

Similarly, using, as the starting material, 4-benzyl piperidinylindole-6-carboxamide or 6-methoxy-(4-benzylpiperidinyl)indole-5-carboxamide, the corresponding 3-trifluoroacetylderivatives were prepared.

B. 4-benzylpiperidinyl indole-5-carboxamide-3-carboxylic acid: Thetrifluoroacetyl indole derivative from paragraph A was suspended inaqueous sodium hydroxide (10 N, 5-6 eq.) And brought to reflux. Uponcommencement of reflux a minimal amount of methanol was added tofacilitate solubility. The reaction mixture was maintained at reflux for3-6 hrs. Upon completion the reaction mixture was cooled to roomtemperature and diluted with water, and washed with ether. The aqueouslayer was then acidified to pH4 with conc. HCl while placed in an icebath. The acid was then extracted into ethyl acetate and washed withsatd. Sodium chloride solution, dried over anhydrous sodium sulfate andconcentrated to give a solid. This solid was purified by chromatographyon silica using ethyl acetate:hexanes:methanol:acetic acid, 5:5:1:0.1.The identity of the product was determined by electron impact massspectroscopy. (MH⁺ 361 (exp. 361), 317, base peak 144.)

Similarly, the additional 3-fluoroacetyl derivatives prepared inparagraph A were converted to the corresponding 3-carboxylic acids.

C.3-(2-dimethylamino)ethylaminocarboxamidyl-(4-benzylpiperidinyl)indole-5-carboxamide:The carboxylic acid of paragraph B (1 eq.) was treated with 1.1equivalent of EDAC.HCl and 1 eq. Of dimethylaminoethylenediamine in thepresence of a catalytic amount of DMAP in DMF/DCM 1:1 for 3-6 hrs. Thereaction mixture was then concentrated and taken up in ethyl acetate.After washing with 5% aq. Sodium carbonate and a solution of saturatedsodium chloride, the organic layer was dried over anhydrous sodiumsulfate and concentrated to give crude material. This crude material waspurified by chromatography on silica. The identity of the product, shownbelow, was determined by electron impact mass spectroscopy. (MH⁺ 432(exp. 432).)

D. Similarly, making the appropriate substitutions for the carboxamideand for the reactive amine, the following compounds of the inventionwere prepared according to the reaction scheme set forth at thebeginning of this example; all are of the formula set forth above, butwith alternative substituents on the carbonyl moiety at the 3-positionof the indole moiety as noted.

i.3-(2-methoxyethylaminocarboxamidyl)-(4-benzylpiperidinyl)indole-5-carboxamide(3-carbonyl substituent is 2-methoxy ethylamino, MH⁺ 418, exp 418);

ii.3-(2-methylaminoethylaminocarboxamidyl)-(4-benzylpiperidinyl)indole-5-carboxamide(3-carbonyl substituent is 2-methylamino ethylamino, MH⁺ 418, exp 418);

iii.3-(N-methyl-2-aminoethylaminocarboxamidyl)-(4-benzylpiperidinyl)indole-5-carboxamide(3-carbonyl substituent is 2-aminoethyl (methyl)amino, MH⁺ 418, exp418);

iv.3-(4-benzylpiperidinylcarboxamidyl)-(4-benzylpiperidinyl)indole-5-carboxamide(3-carbonyl substituent is 4-benzyl piperidinyl, MH⁺ 519, exp 519);

v.3-(4-benzylpiperidinylcarboxamidyl)-(4-benzylpiperidinyl)indole-6-carboxamide(3-carbonyl substituent is 4-benzyl piperidinyl, MH⁺ 519, exp 519);

vi.3-(4-fluorobenzylaminocarboxamidyl)-(4-benzylpiperidinyl)indole-5-carboxamide(3-carbonyl substituent is 4-fluorobenzylamino,MH⁺ 469, exp 469);

vii.3-2-(3,4-dimethoxyphenyl)ethylaminocarboxamidyl-(4-benzylpiperidinyl)indole-5-carboxamide(3-carbonyl substituent is 2-(3,4-dimethoxyphenyl)ethylamino, MH⁺ 525,exp 525);

viii. 3-trifluoroacetyl-(4-benzylpiperidinyl)indole-5-carboxamide(3-carbonyl substituent is trifluoromethyl, MH⁺ 413, exp 414);

ix. 3-trifluoroacetyl-(4-benzylpiperidinyl)indole-6-carboxamide(3-carbonyl substituent is trifluoromethyl, MH⁺ 413, exp 414);

x.6-methoxy-3-(2-dimethylaminoethylamino)carboxamidyl-(4-benzylpiperidinyl)indole-5-carboxamide(3-carbonyl substituent is 2-dimethylaminoethyl, including also a6-methoxy substituent in the 6-position, MH⁺ 462, exp 462).

The formulas of compounds i-x set forth above are shown below.

Alternatively, compounds of the invention which are derivatives ofindole with substitutions at position 3 can be prepared using ReactionScheme 8 set forth previously.

E. Preparation of3-Morpholinomethyl-(4-benzylpiperidinyl)-indole-5-carboxamide:

Using Scheme 8, 0.318 g (1 mmol) of4-benzylpiperidinyl-indole-5-carboxamide, 0.1 g paraformaldehyde (3.3mmol) and 0.1 mL morpholine was taken in 25 mL abs. Ethanol and wasacidified by the addition of 1 mL ethanolic HCl. The mixture wasrefluxed for 18 h. The solvent was removed and the residue was extractedfrom 5% sodiumcarbonate solution with dichloromethane. The extract wasdried, evaporated and the residue was purified by column chromatographyusing ethyl acetate-methanol (95:5). To yield 0.15 g of the desiredproduct. Ir was converted to the HCl salt and lyophilized. M⁺ 454.

F. Preparation ofDiethylaminomethyl-(4-benzylpiperidinyl)-indole-5-carboxamide:

Using Scheme 8, this compound was prepared as follows. To a suspensionof 0.41 g (1.28 mmol) 4-benzylpiperidinyl-indole-5-carboxamide in 5 mLglacial acetic acid was added an ice cooled mixture of 1.2 mL aqueousformaldehyde (37%) and 0.16 mL of ethylamine (1.5 mmol). The reactionmixture was stirred for 30 Min. at 0° C. and then continued stirring atRT for 18 h. It was poured in to water, made basic by the addition of20% sodium hydroxide solution and extracted with ethyl acetate. Theextract was dried and evaporated. The residue was purified bychromatography on silica gel eluting withchloroform-methanol-triethylamine (95:5:0.5) to yield 0.22 g of thetitle compound. MS: 403, M⁺; 331, M⁺−NEt₂.

G. Preparation of6-Methoxy-(4-benzylpiperidinyl)-indole-5-carboxamide-3-glyoxylic acid.

This compound was prepared according to Scheme 9. 0.348 mg (1 mmol) of6-methoxy-(4-benzylpiperidinyl)-indole-5-carboxamide was dissolved in 15mL dry dichloromethane and was cooled to 0° C. in an ice bath 0.6 mL ofa 2 molar solution of oxalylchloride in dichloromethane (Aldrich) wasadded dropwise using a syringe under inert atmosphere and the mixturewas stirred at 0° C. for an h. The ice bath was removed and the mixturestirred further an h. at room temperature. The solvent was evaporatedand the residue dried under vacuum for 30 Min. The solid obtained wasdissolved in a mixture of THF/water and basified with 20% aq. NaOH. Thesolvents were removed and the residue dissolved in water and acidifiedwith conc. HCl. The precipitated solid was collected by filtration,dried and recrystallized from ethanol/water to yield 350 mg of the titlecompound. ESMS. 421, M⁺.

H.6-Methoxy-(4-benzylpiperidinyl)-5-carboxamido-indole-3-glyoxalicacid-4-methylpiperazinamide.

This compound was prepared using the same procedure used above for thecorresponding acid, but substituting 4-methylpiperazine for aq. NaOH andcarrying out the reaction in dry dichloromethane instead of THF/water.ESMS. 503, M⁺.

I.6-Methoxy-(4-benzylpiperidinyl)-5-carboxamido-indole-3-glyoxalicacid-1-(2-aminoethylpyrrolidine)-amide.

This compound was prepared using the same procedure used above, butsubstituting 1-(2-aminoethyl)-pyrrolidine for 4-methylpiperazine. MS.M⁺, 517.

J. 4-Benzylpiperidinyl-5-carboxamido-indole-3-glyoxylicamide.

0.318 g, 1 mmol, of 4-benzylpiperidinyl-indole-5-carboxamide wasdissolved in dry dichloromethane and was reacted with 0.6 mL 2 molarsolution of oxalylchloride at 0° C. for 1 h under nitrogen. Cooling wasremoved and the mixture was stirred an additional 1 h. at RT. Thesolvent was evaporated and the residue dried under vacuum for 30Minutes. The product was redissolved in THF and excess of coc. ammoniawas added. After stirring for 1 h. the solvent was removed and theresidue recrystallized from ethylacetate-hexane. Yield; 220 mg. MS. M⁺,389; 345, M⁺−CONH₂.

K.6-Chloro-(4′-fluoro-4-benzylpiperidinyl)-5-carboxamido-indole-3-glyoxylicacid,4-Methylpiperazinamide.

Prepared using similar procedure described before. MS. M⁺, 524.

EXAMPLE 22 Assay for p38 Kinase Inhibition

The compounds to be tested were solubilized in DMSO and diluted intowater to the desired concentrations. The p38 kinase was diluted to 10μg/ml into a buffer containing 20 mM MOPS, pH 7.0, 25 mM beta-glycerolphosphate, 2 mg/ml gelatin, 0.5 mM EGTA, and 4 mM DTT.

The reaction was carried out by mixing 20 μl test compound with 10 μl ofa substrate cocktail containing 500 μg/ml peptide substrate and 0.2 mMATP (+200 μCi/ml gamma-32P-ATP) in a 4×assay buffer. The reaction wasinitiated by the addition of 10 μl of p38 kinase. Final assay conditionswere 25 mM MOPS, pH 7.0, 26.25 mM beta-glycerol phosphate, 80 mM KCl, 22mM MgCl₂, 3 mM MgSO₄, 1 mg/ml gelatin, 0.625 mM. EGTA, 1 mM DTT, 125μg/ml peptide substrate, 50 μM ATP, and 2.5 μg/ml enzyme. After a 40minute incubation at room temperature, the reaction was stopped by theaddition of 10 μl per reaction of 0.25 M phosphoric acid.

A portion of the reaction was spotted onto a disk of P81phosphocellulose paper, the filters were dried for 2 minutes and thenwashed 4× in 75 mM H₃PO₄. The filters were rinsed briefly in 95%ethanol, dried, then placed in scintillation vials with liquidscintillation cocktail.

Alternatively, the substrate is previously biotinylated and theresulting reactions are spotted on SAM^(2TM) streptavidin filter squares(Promega). The filters are washed 4× in 2M NaCl, 4× in 2M NaCl with 1%phosphoric acid, 2× in water, and briefly in 95% ethanol. The filtersquares are dried and placed in scintillation vials with liquidscintillation cocktail.

Counts incorporated are determined on a scintillation counter. Relativeenzyme activity is calculated by subtracting background counts (countsmeasured in the absence of enzyme) from each result, and comparing theresulting counts to those obtained in the absence of inhibitor. IC₅₀values were determined with curve-fitting plots available with commonsoftware packages. Approximate IC₅₀ values were calculated using formula

IC ₅₀(app)=(A×i)/(1−A)

where A=fractional activity and i=total inhibitor concentration.

EXAMPLE 23 Activity of the Invention Compounds

The activity of the invention compounds was tested as described above.The compounds tested were 4-benzylpiperidinyl or 4-benzylpiperazinylindole-5- or 6-carboxamides. In general, the piperidinyl derivative wassuperior to the corresponding piperazinyl. The IC₅₀ for inhibition ofp38α is shown in Table 1.

TABLE 1 Ring Piperidinyl Piperazinyl position IC₅₀ μM IC₅₀ μM 5 0.150,0.242 1.71, 1.78 6 0.462, 0.462 5.52, 4.97 3 0.2 5.44 4 0.2 1.55 23.26 >30 7 >30 >30

It is also seen that positioning the piperidinyl or piperazinylsubstituent in positions 3, 4, 5 and 6 leads to greater activity thanpositioning the substituents in positions 2 or 7.

The same compounds were tested for their specificity for p38α ascompared to p38β. The results are shown in Table 2.

TABLE 2 Piperidinyl Piperazinyl Ring P38-β p38α IC₅₀ ratio P38-β p38-αIC₅₀ ratio position IC₅₀ μM IC₅₀ μM β/α IC₅₀ μM IC₅₀ μM β/α 5 3.02 0.15020.1 25.8 1.71 15.1 6 3.83 0.462 8.27 39.1 5.52 7.08

Activity with regard to p38β was also tested for compounds of theinvention to determine the influence of the position of the piperidinylor piperazinyl substituent. The influence of substitution on the benzylmoiety attached to the 4-position of the piperazine or piperidine wasalso tested. The results are shown in Table 3 in terms of the percentinhibition of p38β activity at 50 μM concentration of the compound.

TABLE 3 Ring position Benzyl substitution Piperidinyl Piperazinyl 5 — 9659 6 — 92 56 3 — 96 77 4 — 96 68 2 — 12 27 7 — 45 7 5 4-Cl 77

Substituting benzimidazole for the indole moiety in the compounds of theinvention also resulted in significant inhibition of p38β when thecompounds were tested at 50 μM. 4-Benzyl piperidinylbenzimidazole-5-carboximide showed 85% inhibition;4-(3-chlorobenzyl)piperizinyl benzimidazole-5-carboxamide showed 66%inhibition.

The compounds of the invention, generally, are specific for p38α ascompared to p38-β: It is seen that the specificity for α as opposed to βis generally of the order of ten-fold.

The specificity of the compounds of the invention was also tested withrespect to other kinases, including p38-γ, ERK-2, PKA, PKC, cdc-2,EGF-R, and DNA-PK as shown in Table 4. The compounds tested are the4-benzylpiperidinyl indole-5- and 6-carboximides with the numberindicating the ring position of the carboxamide.

TABLE 4 IC₅₀ μM IC₅₀ μM KINASE 5 6 p38-α 0.150 0.462 p38-γ 228 >300ERK-2 >300 >300 PKA 430 >500 PKC >500 >500 cdc2 >500 >500EGF-R >500 >500 DNA-PK >500 450

The results are given in terms of approximate IC₅₀ (μM) values when thecompounds were tested at 50 μM and calculated using the formula inExample 22. The exception is for p38α values where the IC₅₀ values weredetermined from concentration dependent curve fitting analysis.

As shown, all of the compounds tested are highly specific for p38α ascompared to these additional kinases.

Table 5 shows the inhibition of p38α by invention compounds that are4-(benzylpiperidinyl)indole-5-carboxamides or4-[(4-fluorobenzyl)piperidinyl]indole-5-carboxamides, i.e., compounds offormulas (1) or (2):

wherein R¹ is of formula (11) or (12):

The values given are IC₅₀ in μM.

TABLE 5 Formula R³ R¹ R² Z¹ Z² IC₅₀ 1 H (11) H N CH 0.635 1 H (11) H CHCH 0.523, 0.577 2 CH₃O (12) H CH CH 0.159 2 Cl (11) Et₂N(CH₂)₃— CH CH0.199 1 H (12) Et₂N(CH₂)₂— CH CH 0.354 2 CH₃O (11) H CCONH(CH₂)₂NMe₂ CH0.0646 1 H (12) H N CH 0.39 1 H (11) H

CH 6.57 1 H (11)

CH CH 0.871 1 H (11)

CH CH 0.405 1 H (11)

CH CH 0.8 1 MeO (12) H

0.242 1 Cl (11) H CH CCH₃ 0.489 1 H (11) Et₂N(CH₂)₃— CH CH 0.474 1 H(11) H

0.33 1 H (12) H

0.243 2 MeO (11) Et₂N(CH₂)₂— CH CH 0.184 1 Cl (11) H CH CCH₃ (43% at 0.2μM)

Several other compounds of the invention were also tested. A compound offormula (3)—i.e., where the carboximide is in the 6-position, R¹ is offormula (11), R³ is H, R² is H. Z¹ is CCOCF₃ and Z² is CH showed 41%inhibition at 1 μM. Similarly, a compound where R¹ is of formula (11)and substituted at the 6-position of the indole, R²

and both Z¹ and Z² are CH, showed an IC₅₀ of 0.505 μM.

Two compounds where R¹ is of the formula:

were also tested. In one, of formula (2) wherein R³ is MeO, R² is H andboth Z¹ and Z² are CH, gave 63% inhibition at 0.2 μM; in the other case,which is of formula (3) wherein R³ is H, R² is H, Z¹ is N and Z² is CH,the IC₅₀ was 2.15 μM. Finally, one compound was tested wherein R¹ was ofthe formula:

and wherein the invention compound is of formula (3) wherein R³ is H, R²is H, and both Z¹ and Z² are CH, gave 51% inhibition at 1 μm.

What is claimed is:
 1. A compound of the formula:

and the pharmaceutically acceptable salts thereof, wherein each of Z¹and Z² is independently CR⁴ or N; where each R⁴ is independentlyselected from the group consisting of H, alkyl (1-6C) and aryl, each ofsaid alkyl and aryl optionally including one or more heteroatomsselected from O, S, and N and each of said alkyl being optionallysubstituted by one or more substituents selected from the groupconsisting of halo, OR, SR, NR₂, RCO, COOR, CONR₂, OOCR, NROCR, CN, ═O,a five- or six-membered saturated carbocyclic ring or heterocyclic ringcontaining 1-2 N, and a six-membered aromatic ring optionally containing1-2 N, where R in the foregoing optional substituents is H or alkyl(1-6C) and each of said aryl being optionally substituted by one or moresubstituents selected from the group consisting of halo, OR, SR, NR₂,RCO, COOR, CONR₂, OOCR, NROCR, CN, a five- or six-membered saturatedcarbocyclic ring or heterocyclic ring containing 1-2 N, and asix-membered aromatic ring optionally containing 1-2 N, where R in theforegoing optional substituents is H or alkyl (1-6C); or R¹ is

 wherein X¹ is CO, SO, SO₂ or CHOH; m is 1; Y is optionally substitutedalkyl, optionally substituted aryl, or optionally substituted arylalkylor two Y taken together may form an alkylene (2-3C) bridge; n is 0, 1 or2; Z³ is N; X² is CH, CH₂ or an isostere thereof; and Ar consists of oneor two phenyl moieties directly coupled to X², said one or two phenylmoieties being optionally substituted by one or more substituentsselected from the group consisting of halo, nitro, alkyl (1-6C), alkenyl(1-6C), alkynyl (1-6C), CN, CF₃, RCO, COOR, CONR₂, NR₂, OR, SR, OOCR,NROCR; and phenyl, itself optionally substituted by one or more of theforegoing substituents, wherein R in the foregoing optional substituentsis H or alkyl (1-6C); R² is selected from the group consisting of H,alkyl (1-6C) and aryl, each of said alkyl or aryl optionally includingone or more heteroatoms which are selected from O, S and N, and each ofsaid alkyl being optionally substituted by one or more substituentsselected from the group consisting of halo, OR, SR, NR₂, RCO, COOR,CONR₂, OOCR, NROCR, CN, ═O, a five- or six-membered saturatedcarbocyclic ring or heterocyclic ring containing 1-2 N, and asix-membered aromatic ring optionally containing 1-2 N, where R in theforegoing optional substituents is H or alkyl (1-6C) and each of saidaryl being optionally substituted by one or more substituents selectedfrom the group consisting of halo, OR, SR, NR₂, RCO, COOR, CONR₂, OOCR,NROCR, CN, a five- or six-membered saturated carbocyclic ring orheterocyclic ring containing 1-2 N, and a six-membered aromatic ringoptionally containing 1-2 N, where R in the foregoing optionalsubstituents is H or alkyl (1-6C) with the proviso that when both Z¹ andZ² are CH, R² is other than H; R³ is selected from the group consistingof H, halo, NO₂, alkyl (1-6C), alkenyl (1-6C), alkynyl (1-6C), CN, OR,SR, NR₂, RCO, COOR, CONR₂, OOCR, and NROCR where R is H or alkyl (1-6C).2. The compound of claim 1 which is of the formula


3. The compound of claim 1 wherein R² is alkyl (1-6C) or aryl, each ofsaid alkyl or aryl optionally including one or more heteroatoms whichare selected from O, S and N, and each of said alkyl being optionallysubstituted by one or more substituents selected from the groupconsisting of halo, OR, SR, NR₂, RCO, COOR, CONR₂, OOCR, NROCR, CN, ═O,a five- or six-membered saturated carbocyclic ring or heterocyclic ringcontaining 1-2 N, and a six-membered aromatic ring optionally containing1-2 N, where R in the foregoing optional substituents is H or alkyl(1-6C) and each of said aryl being optionally substituted by one or moresubstituents selected from the group consisting of halo, OR, SR, NR₂,RCO, COOR, CONR₂, OOCR, NROCR, CN, a five- or six-membered saturatedcarbocyclic ring or heterocyclic ring containing 1-2 N, and asix-membered aromatic ring optionally containing 1-2 N, where R in theforegoing optional substituents is H or alkyl (1-6C).
 4. The compound ofclaim 1 wherein X¹ is CO.
 5. The compound of claim 1 wherein X² is CH₂.6. The compound of claim 2 wherein X¹ is CO and X² is CH₂.
 7. Thecompound of claim 1 wherein Z¹ and Z² are CR⁴.
 8. The compound of claim6 wherein Z¹ and Z² are CR⁴.
 9. The compound of claim 1 wherein Z¹ is Nand Z² is CH.
 10. The compound of claim 6 wherein Z¹ is N and Z² is CH.11. The compound of claim 2 which is of the formula (2).
 12. Thecompound of claim 6 which is of the formula (2).
 13. The compound ofclaim 2 wherein R³ is halo or OR where R is alkyl (1-6C).
 14. Thecompound of claim 6 wherein R³ is halo or OR where R is alkyl (1-6C);and wherein R² is alkyl (1-6C) or is aryl, each of said alkyl or arylconstituting the substituent R² optionally including one or moreheteroatoms which are selected from O, S and N, and each said alkyloptionally substituted by one or more substituents selected from thegroup consisting of halo, OR, SR, NR₂, RCO, COOR, CONR₂, OOCR, NROCR(where R is H or 1-6C alkyl), CN, ═O, a five- or six-membered saturatedcarbocyclic ring or heterocyclic ring containing 1-2 N, and asix-membered aromatic ring optionally containing 1-2 N and each of saidaryl being optionally substituted by one or more substituents selectedfrom the group consisting of halo, OR, SR, NR₂, RCO, COOR, CONR₂, OOCR,NROCR, CN, a five- or six-membered saturated carbocyclic ring orheterocyclic ring containing 1-2 N, and a six-membered aromatic ringoptionally containing 1-2 N, where R in the foregoing optionalsubstituents is H or alkyl (1-6C).
 15. The compound of claim 1 whereinAr is

wherein each X³ is independently alkyl (1-6C), halo, OR, or NR₂ and p is0, 1, 2 or
 3. 16. The compound of claim 6 wherein Ar is

wherein each X³ is independently alkyl (1-6C), halo, OR, or NR₂ and p is0, 1, 2 or
 3. 17. A compound which is selected from the group consistingof: 4-(2,6-difluorobenzyl)-piperazinyl-benzymidazole-5-carboxamide;4-(2,3-difluorobenzyl)-piperazinyl-benzimidazole-5-carboxamide;4-(3,5-difluorobenzyl)-piperazinyl-benzimidazole-5-carboxamide;4-(3-chlorobenzyl)-piperazinyl-benzimidazole-5-carboxamide;4-(4-carboxymethyl benzyl)-piperazinyl-benzimidazole-5-carboxamide;4-(4-methoxybenzyl)-piperazinyl-benzimidazole-5-carboxamide;4-(4-trifluoxomethoxybenzyl)-piperazinyl-benzimidazole-5-carboxamide;4-(4-methylbenzyl)-piperazinyl-benzimidazole-5-carboxamide;4-(2,4-dichlorobenzoyl)-piperazinyl-benzimidazole-5-carboxamide;4-(3,4-dichlorobenzoyl)-piperazinyl-benzimidazole-5-carboxamide;4-[trans-3-(trifluoromethyl)-cinnamoyl]-piperazinyl-benzimidazole-5-carboxamide;4-(4-chlorobenzoyl)-piperazinyl-benzimidazole-5-carboxamide;4-benzoylpiperazine-benzimidazole-5-carboxamide;4-(2-trifluoromethylbenzoyl)-piperazinyl-benzimidazole-5-carboxamide;4-(4-methoxybenzoyl)-piperazinyl-benzimidazole-5-carboxamide;4-(3,4-dichlorophenyl)-piperazinyl-benzimidazole-5-carboxamide;4-(4-chlorobenzhydryl)-piperazinyl-benzimidazole-5-carboxamide;4-trans-1-cinnamyl piperazinyl-benzimidazole-5-carboxamide;4-[bis(4-fluorophenyl)-methyl]-piperazinyl-benzimidazole-5-carboxamide;4-(4-chlorobenzyl)-piperazinyl-benzimidazole-5-carboxamide;4-(2-chlorobenzyl)-piperazinyl-benzimidazole-5-carboxamide;4-benzylpiperazinyl-benzimidazole-5-carboxamide;4-(4-methylthiobenzyl)-piperazinyl-benzimidazole-5-carboxamide;4-(3,4,5-trimethoxybenzyl)-piperazinyl-benzimidazole-5-carboxamide;4-(4-diethylaminobenzyl)-piperazinyl-benzimidazole-5-carboxamide;4-(biphenylmethyl)-piperazinyl-benzimidazole-5-carboxamide;4-(4-Phenoxybenzyl)-piperazinyl-benzimidazole-5-carboxamide;4-(4-chlorobenzyl)-piperazinyl-1-(2-propyl)-indole-5-carboxamide;4-(3-chlorobenzyl)-piperazinyl-N-benzyl-benzimidazole-5-carboxamide;4-(3-chlorobenzyl)-piperazinyl-N-benzyl-benzimidazole-6-carboxamide;4-(3-chlorobenzyl)-piperazinyl-N-(2-propyl)-benzimidazole-5-carboxamide;4-(3-chlorobenzyl)-piperazinyl-N-(2-propyl)-benzimidazole-6-carboxamide;4-(3-chlorobenzyl)-piperazinyl-N-ethyl-benzimidazole-5-carboxamide;4-(3-chlorobenzyl)-piperazinyl-N-ethyl-benzimidazole-6-carboxamide;4-(3-chlorobenzyl)-piperazinyl-N-methyl-benzimidazole-5-carboxamide; and4-(3-chlorobenzyl)-piperazinyl-N-methyl-benzimidazole-6-carboxamide. 18.The compound of claim 1 wherein Z² is CH and wherein R² is alkyl (1-6C)or is aryl, each of said alkyl or aryl constituting the substituent R²optionally including one or more heteroatoms which are selected from O,S and N, and each said alkyl optionally substituted by one or moresubstituents selected from the group consisting of halo, OR, SR, NR₂,RCO, COOR, CONR₂, OOCR, NROCR (where R is H or 1-6C alkyl), CN, ═O, afive- or six-membered saturated carbocyclic ring or heterocyclic ringcontaining 1-2 N, and a six-membered aromatic ring optionally containing1-2 N and each of said aryl being optionally substituted by one or moresubstituents selected from the group consisting of halo, OR, SR, NR₂,RCO, COOR, CONR₂, OOCR, NROCR, CN, a five- or six-membered saturatedcarbocyclic ring or heterocyclic ring containing 1-2 N, and asix-membered aromatic ring optionally containing 1-2 N, where R in theforegoing optional substituents is H or alkyl (1-6C).
 19. The compoundof claim 1 wherein Z¹ is CR⁴ and R⁴ is other than H.
 20. The compound ofclaim 1 wherein Z¹ is CR⁴ wherein R⁴ is other than H and Z² is CH. 21.The compound of claim 20 wherein R⁴ is alkyl optionally containing oneor more heteroatoms selected from O, S and N, said alkyl beingoptionally substituted by one or more substituents selected from thegroup consisting of halo, OR, SR, NR₂, RCO, COOR, CONR₂, OOCR, NROCR,CN, ═O, a five- or six-membered saturated carbocyclic ring orheterocyclic ring containing 1-2 N, and a six-membered aromatic ringoptionally containing 1-2 N, where R in the foregoing optionalsubstituents is H or alkyl (1-6C).
 22. The compound of claim 21 whereinR⁴ contains the structure


23. The compound of claim 22 which is of the formula


24. The compound of claim 23 which is of the formula (2).
 25. Thecompound of claim 21 wherein Ar is

wherein each X³ is independently alkyl (1-6C), halo, OR; or NR₂ and p is0, 1, 2 or
 3. 26. The compound of claim 21 wherein R³ is halo or ORwhere R is alkyl (1-6C).
 27. The compound of claim 21 wherein R² is H oralkyl (1-6C).
 28. The compound of claim 21 wherein R⁴ contains NR₂. 29.The compound of claim 21 wherein R⁴ contains a saturated 5 or 6 memberedring containing 1-2 heteroatoms.
 30. The compound of claim 21 wherein R⁴contains an unsaturated 5 or 6 membered ring containing 1-2 heteroatoms.31. The compound of claim 25 wherein R⁴ contains ═O.
 32. The compound ofclaim 31 wherein R⁴ contains the structure:


33. A compound of the formula:

and the pharmaceutically acceptable salts thereof, wherein each of Z¹and Z² is independently CR⁴ or N; where each R⁴ is independentlyselected from the group consisting of H, alkyl (1-6C) and aryl, each ofsaid alkyl and aryl optionally including one or more heteroatomsselected from O, S, and N and each of said alkyl being optionallysubstituted by one or more substituents selected from the groupconsisting of halo, OR, SR, NR₂, RCO, COOR, CONR₂, OOCR, NROCR, CN, ═O,a five- or six-membered saturated carbocyclic ring or heterocyclic ringcontaining 1-2 N, and a six-membered aromatic ring optionally containing1-2 N, where R in the foregoing optional substituents is H or alkyl(1-6C) and each of said aryl being optionally substituted by one or moresubstituents selected from the group consisting of halo, OR, SR, NR₂,RCO, COOR, CONR₂, OOCR, NROCR, CN, a five- or six-membered saturatedcarbocyclic ring or heterocyclic ring containing 1-2 N, and asix-membered aromatic ring optionally containing 1-2 N, where R in theforegoing optional substituents is H or alkyl (1-6C); or R¹ is

 wherein X¹ is CO or an isostere thereof, m is 1; Y is optionallysubstituted alkyl, optionally substituted aryl, or optionallysubstituted arylalkyl or two Y taken together may form an alkylene(2-3C) bridge; n is 0, 1 or 2; Z³ is N; X² is CH, CH₂ or an isosterethereof; and Ar is a phenyl moiety optionally substituted by asubstituent selected from halo, nitro, alkyl (1-6C), alkenyl (1-6C),alkynyl (1-6C), CN, CF₃, RCO, COOR, CONR₂, NR₂, OR, SR, OOCR, NROCR, andphenyl, itself optionally substituted by the foregoing substituents,wherein R in the foregoing optional substituents is H or alkyl (1-6C);R² is selected from the group consisting of H, alkyl (1-6C) and aryl,each of said alkyl and aryl optionally including one or more heteroatomswhich are selected from O, S and N, and each of said alkyl beingoptionally substituted by one or more substituents selected from halo,OR, SR, NR₂, RCO, COOR, CONR₂, OOCR, NROCR, CN, ═O, a five- orsix-membered saturated carbocyclic ring or heterocyclic ring containing1-2 N, and a six-membered aromatic ring optionally containing 1-2 N,where R in the foregoing optional substituents is H or alkyl (1-6C) andeach of said aryl being optionally substituted by one or moresubstituents selected from the group consisting of halo, OR, SR, NR₂,RCO, COOR, CONR₂, OOCR, NROCR, CN, a five- or six-membered saturatedcarbocyclic ring or heterocyclic ring containing 1-2 N, and asix-membered aromatic ring optionally containing 1-2 N, where R in theforegoing optional substituents is H or alkyl (1-6C) with the provisothat if both Z¹ and Z² are CH, R² is other than H; R³ is selected fromthe group consisting of H, halo, NO₂, alkyl (1-6C), alkenyl (1-6C),alkynyl (1-6C), CN, OR, SR, NR₂, RCO, COOR, CONR₂, OOCR, and NROCR whereR is H or alkyl (1-6C).
 34. The compound of claim 33 wherein Z¹ is CR⁴wherein CR⁴ is other than H.
 35. The compound of claim 33 wherein Z² isCH and wherein R² is alkyl (1-6C) or is aryl, each of said alkyl or arylconstituting the substituent R² optionally including one or moreheteroatoms which are selected from O, S and N, and said alkyloptionally substituted by one or more substituents selected from thegroup consisting of halo, OR, SR, NR₂, RCO, COOR, CONR₂, OOCR, NROCR(where R is H or 1-6C alkyl), CN, ═O, a five- or six-membered saturatedcarbocyclic ring or heterocyclic ring containing 1-2 N, and asix-membered aromatic ring optionally containing 1-2 N and each of saidaryl being optionally substituted by one or more substituents selectedfrom the group consisting of halo, OR, SR, NR₂, RCO, COOR, CONR₂, OOCR,NROCR, CN, a five- or six-membered saturated carbocyclic ring orheterocyclic ring containing 1-2 N, and a six-membered aromatic ringoptionally containing 1-2 N, where R in the foregoing optionalsubstituents is H or alkyl (1-6C).
 36. The compound of claim 33 whereinZ¹ and Z² are both CR⁴.
 37. The compound of claim 33 wherein Z¹ is CR⁴wherein CR⁴ is other than H and Z² is CH.
 38. The compound of claim 37which is of the formula


39. The compound of claim 38 which is of the formula (2).
 40. Thecompound of claim 39 wherein Ar is

wherein each X³ is independently alkyl (1-6C), halo, —OR, or NR₂ and pis 0, 1, 2 or
 3. 41. The compound of claim 39 wherein R³ is halo or ORwhere R is alkyl (1-6C).
 42. The compound of claim 39 wherein R² is H oralkyl (1-6C).
 43. The compound of claim 37 wherein R⁴ is alkyloptionally containing one or more heteroatoms selected from O, S and Nand said alkyl is optionally substituted by one or more substituentsselected from the group consisting of halo, OR, SR, NR₂, RCO, COOR,CONR₂, OOCR, NROCR, CN, ═O, a five- or six-membered saturatedcarbocyclic ring or heterocyclic ring containing 1-2 N, and asix-membered aromatic ring optionally containing 1-2 N, where R in theforegoing optional substituents is H or alkyl (1-6C).
 44. The compoundof claim 43 wherein R⁴ contains NR₂.
 45. The compound of claim 43wherein R⁴ contains a saturated 5- or 6-membered ring containing 1-2heteroatoms.
 46. The compound of claim 43 wherein R⁴ contains anunsaturated 5- or 6-membered ring containing 1-2 heteroatoms.
 47. Thecompound of claim 43 wherein R⁴ contains ═O.
 48. The compound of claim47 wherein R⁴ contains the structure.
 49. A compound of the formula:

and the pharmaceutically acceptable salts thereof, wherein Z¹ is CR^(4′)and Z² is CH; where R^(4′) is selected from the group consisting ofalkyl (1-6C) and aryl, each of said alkyl and aryl optionally includingone or more heteroatoms selected from O, S, and N and each of said alkylbeing optionally substituted by one or more substituents selected fromthe group consisting of halo, OR, SR, NR₂, RCO, COOR, CONR₂, OOCR,NROCR, CN, ═O, a five- or six-membered saturated carbocyclic ring orheterocyclic ring containing 1-2 N, and a six-membered aromatic ringoptionally containing 1-2 N, where R in the foregoing optionalsubstituents is H or alkyl (1-6C) and each of said aryl being optionallysubstituted by one or more substituents selected from the groupconsisting of halo, OR, SR, NR₂, RCO, COOR, CONR₂, OOCR, NROCR, CN, afive- or six-membered saturated carbocyclic ring or heterocyclic ringcontaining 1-2 N, and a six-membered aromatic ring optionally containing1-2 N, where R in the foregoing optional substituents is H or alkyl(1-6C); or R¹ is

 wherein X¹ is CO or an isostere thereof; m is 1; Y is optionallysubstituted alkyl, optionally substituted aryl, or optionallysubstituted arylalkyl or two Y taken together may form an alkylene(2-3C) bridge; n is 0, 1 or 2; Z³ is N; X² is CH, CH₂ or an isosterethereof; and Ar is one or two phenyl moieties, optionally substituted byone or more substituents selected from halo, nitro, alkyl (1-6C),alkenyl (1-6C), alkynyl (1-6C), CN, CF₃, RCO, COOR, CONR₂, NR₂, OR, SR,OOCR, NROCR, and phenyl itself optionally substituted by the foregoingsubstituents, wherein R in the foregoing optional substituents is H oralkyl (1-6C); R² is selected from the group consisting of H, alkyl(1-6C) and aryl, each of said alkyl or aryl optionally including one ormore heteroatoms which are selected from O, S and N, and each of saidalkyl being optionally substituted by one or more substituents selectedfrom the group consisting of halo, OR, SR, NR₂, RCO, COOR, CONR₂, OOCR,NROCR, CN, ═O, a five- or six-membered saturated carbocyclic ring orheterocyclic ring containing 1-2 N, and a six-membered aromatic ringoptionally containing 1-2 N, where R in the foregoing optionalsubstituents is H or alkyl (1-6C) and each of said aryl being optionallysubstituted by one or more substituents selected from the groupconsisting of halo, OR, SR, NR₂, RCO, COOR, CONR₂, OOCR, NROCR, CN, afive- or six-membered saturated carbocyclic ring or heterocyclic ringcontaining 1-2 N, and a six-membered aromatic ring optionally containing1-2 N, where R in the foregoing optional substituents is H or alkyl(1-6C); R³ is selected from the group consisting of H, halo, NO₂, alkyl(1-6C), alkenyl (1-6C), alkynyl (1-6C), CN, OR, SR, NR₂, RCO, COOR,CONR₂, OOCR, and NROCR where R is H or alkyl (1-6C).
 50. The compound ofclaim 49 where R^(4′) is alkyl optionally substituted by one or moresubstituents selected from the group consisting of halo, OR, SR, NR₂,RCO, COOR, CONR₂, OOCR, NROCR, CN, ═O, a five- or six-membered saturatedcarbocyclic ring or heterocyclic ring containing 1-2 N, and asix-membered aromatic ring optionally containing 1-2 N where R in thepreceding substituents is H or 1-6C alkyl.
 51. The compound of claim 50wherein R^(4′) contains ═O.
 52. The compound of claim 51 wherein R^(4′)contains:


53. The compound of claim 52 where R² is selected from the groupconsisting of alkyl (1-6C) and aryl, each of said alkyl and aryloptionally including one or more heteroatoms selected from O, S and N,and each of and alkyl being optionally substituted by one or moresubstituents selected from the group consisting of halo, OR, SR, NR₂,RCO, COOR, CONR₂, OOCR, NROCR, CN, ═O, a five- or six-membered saturatedcarbocyclic ring or heterocyclic ring containing 1-2 N, and asix-membered aromatic ring optionally containing 1-2 N, where R in theforegoing optional substituents is H or alkyl (1-6C) and each of saidaryl being optionally substituted by one or more substituents selectedfrom the group consisting of halo, OR, SR, NR₂, RCO, COOR, CONR₂, OOCR,NROCR, CN, a five- or six-membered saturated carbocyclic ring orheterocyclic ring containing 1-2 N, and a six-membered aromatic ringoptionally containing 1-2 N, where R in the foregoing optionalsubstituents is H or alkyl (1-6C).
 54. The compound of claim 49 whereR^(4′) is aryl optionally substituted by at least one substituentselected from the group consisting of halo, OR, SR, NR₂, RCO, COOR,CONR₂, OOCR, or NROCR, CN, and a five- or six-membered saturatedcarbocyclic ring or heterocyclic ring containing 1-2 N, and asix-membered aromatic ring optionally containing 1-2 N where R in thepreceding substituents is H or 1-6C alkyl.
 55. The compound of claim 54wherein R⁴′ comprises 4 pyridyl, 2-pyridyl, 3-pyridyl, 2-piperidyl,3-piperidyl, or 4-piperidyl.
 56. The compound of claim 52 wherein Ar is

wherein each X³ is independently alkyl (1-6C), halo, —OR, or NR₂ and pis 0, 1, 2 or
 3. 57. A compound of the formula:

and the pharmaceutically acceptable salts thereof, wherein Z¹ and Z² areeach independently N or CR⁴; where R⁴ is selected from the groupconsisting of H, alkyl (1-6C) and aryl, each of said alkyl and aryloptionally including one or more heteroatoms selected from O, S, and Nand each of said alkyl being optionally substituted by one or moresubstituents selected from the group consisting of halo, OR, SR, NR₂,RCO, COOR, CONR₂, OOCR, NROCR, CN, ═O, a five- or six-membered saturatedcarbocyclic ring or heterocyclic ring containing 1-2 N, and asix-membered aromatic ring optionally containing 1-2 N, where R in theforegoing optional substituents is H or alkyl (1-6C) and each of saidaryl being optionally substituted by one or more substituents selectedfrom the group consisting of halo, OR, SR, NR₂, RCO, COOR, CONR₂, OOCR,NROCR, CN, a five- or six-membered saturated carbocyclic ring orheterocyclic ring containing 1-2 N, and a six-membered aromatic ringoptionally containing 1-2 N, where R in the foregoing optionalsubstituents is H or alkyl (1-6C); or R¹ is

 wherein X¹ is CO or an isostere thereof; m is 1; Y is optionallysubstituted alkyl, optionally substituted aryl, or optionallysubstituted arylalkyl or two Y taken together may form an alkylene(2-3C) bridge; n is 1 or 2; Z³ is N; X² is CH, CH₂ or an isosterethereof; and Ar is one or two phenyl moieties, optionally substituted byone or more substituents selected from halo, nitro, alkyl (1-6C),alkenyl (1-6C), alkynyl (1-6C), CN, CF₃, RCO, COOR, CONR₂, NR₂, OR, SR,OOCR, NROCR, and phenyl, itself optionally substituted by the foregoingsubstituents, wherein R in the foregoing optional substituents is H oralkyl (1-6C); R² is selected from the group consisting of H, alkyl(1-6C) and aryl, each of said alkyl or aryl optionally including one ormore heteroatoms which are selected from O, S and N, and each of saidalkyl being optionally substituted by one or more substituents selectedfrom the group consisting of halo, OR, SR, NR₂, RCO, COOR, CONR₂, OOCR,NROCR, CN, ═O, a five- or six-membered saturated carbocyclic ring orheterocyclic ring containing 1-2 N, and a six-membered aromatic ringoptionally containing 1-2 N, where R in the foregoing optionalsubstituents is H or alkyl (1-6C) and each of said aryl being optionallysubstituted by one or more substituents selected from the groupconsisting of halo, OR, SR, NR₂, RCO, COOR, CONR₂, OOCR, NROCR, CN, afive- or six-membered saturated carbocyclic ring or heterocyclic ringcontaining 1-2 N, and a six-membered aromatic ring optionally containing1-2 N, where R in the foregoing optional substituents is H or alkyl(1-6C); R³ is selected from the group consisting of H, halo, NO₂, alkyl(1-6C), alkenyl (1-6C), alkynyl (1-6C), CN, OR, SR, NR₂, RCO, COOR,CONR₂, OOCR, and NROCR where R is H or alkyl (1-6C).
 58. The compound ofclaim 57 where R⁴ is alkyl optionally substituted by one or moresubstituents selected from the group consisting of halo, OR, SR, NR₂,RCO, COOR, CONR₂, OOCR, NROCR, CN, ═O, and saturate or unsaturated 5- or6-membered rings optionally containing 1-2 heteroatoms where R in thepreceding substituents is H or 1-6C alkyl.
 59. The compound of claim 57wherein R⁴ contains ═O.
 60. The compound of claim 59 wherein R⁴contains:


61. The compound of claim 60 wherein R² is selected from the groupconsisting of alkyl (1-6C) and aryl, each of said alkyl and aryloptionally including one or more heteroatoms selected from O, S and N,and each of said alkyl being optionally substituted by one or moresubstituents selected from the group consisting of halo, OR, SR, NR₂,RCO, COOR, CONR₂, OOCR, NROCR, CN, ═O, a five- or six-membered saturatedcarbocyclic ring or heterocyclic ring containing 1-2 N, and asix-membered aromatic ring optionally containing 1-2 N, where R in theforegoing optional substituents is H or alkyl (1-6C) and each of saidaryl being optionally substituted by one or more substituents selectedfrom the group consisting of halo, OR, SR, NR₂, RCO, COOR, CONR₂, OOCR,NROCR, CN, a five- or six-membered saturated carbocyclic ring orheterocyclic ring containing 1-2 N, and a six-membered aromatic ringoptionally containing 1-2 N, where R in the foregoing optionalsubstituents is H or alkyl (1-6C).
 62. The compound of claim 57 whereinR⁴ is aryl optionally substituted by at least one substituent selectedfrom the group consisting of halo, OR, SR, NR₂, RCO, COOR, CONR₂, OOCR,or NROCR, CN, a five- or six-membered saturated carbocyclic ring orheterocyclic ring containing 1-2 N, and a six-membered aromatic ringoptionally containing 1-2 N where R in the preceding substituents is Hor 1-6C alkyl.
 63. The compound of claim 62 wherein R⁴ comprises2-pyridyl, 3-pyridyl, 4-pyridyl, 2-piperidyl, 3-piperidyl, or4-piperidyl.
 64. A method to treat a condition characterized by apro-inflammation response which method comprises administering to asubject in need of such treatment an amount of a compound of any ofclaims 1, 17, 33, 49 or 57 or a pharmaceutical composition thereofeffective to treat said condition.
 65. The method of claim 64 whereinsaid condition characterized by inflammation is acute respiratorydistress syndrome, asthma, chronic obstructive pulmonary disease,uveitis, IBD, acute renal failure, head trauma, or ischemic/reperfusioninjury.
 66. A method to treat a heart condition associated with cardiacfailure, which method comprises administering to a subject in need ofsuch treatment an amount of a compound of any of claims 1, 17, 33, 49 or57 or a pharmaceutical composition thereof effective to treat said heartcondition.
 67. The method of claim 66 wherein said chronic heartcondition is congestive heart failure, cardiomyopathy or myocarditis.